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August 2020
GLYPHOSATE II
DISCLAIMER
Use of trade names is for identification only and does not imply endorsement by the Agency for Toxic
Substances and Disease Registry, the Public Health Service, or the U.S. Department of Health and Human
Services.
GLYPHOSATE III
FOREWORD
This toxicological profile is prepared in accordance with guidelines developed by the Agency for Toxic
Substances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA). The
original guidelines were published in the Federal Register on April 17, 1987. Each profile will be
revised and republished as necessary.
The ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects
information for these toxic substances described therein. Each peer-reviewed profile identifies and
reviews the key literature that describes a substance's toxicologic properties. Other pertinent literature is
also presented, but is described in less detail than the key studies. The profile is not intended to be an
exhaustive document; however, more comprehensive sources of specialty information are referenced.
The focus of the profiles is on health and toxicologic information; therefore, each toxicological profile
begins with a relevance to public health discussion which would allow a public health professional to
make a real-time determination of whether the presence of a particular substance in the environment
poses a potential threat to human health. The adequacy of information to determine a substance's health
effects is described in a health effects summary. Data needs that are of significance to the protection of
public health are identified by ATSDR and EPA.
(B) A determination of whether adequate information on the health effects of each substance is
available or in the process of development to determine the levels of exposure that present a
significant risk to human health due to acute, intermediate, and chronic duration exposures;
and
(C) Where appropriate, identification of toxicologic testing needed to identify the types or levels
of exposure that may present significant risk of adverse health effects in humans.
The principal audiences for the toxicological profiles are health professionals at the Federal, State, and
local levels; interested private sector organizations and groups; and members of the public.
This profile reflects ATSDR’s assessment of all relevant toxicologic testing and information that has
been peer-reviewed. Staffs of the Centers for Disease Control and Prevention and other Federal
scientists have also reviewed the profile. In addition, this profile has been peer-reviewed by a
nongovernmental panel and was made available for public review. Final responsibility for the
contents and views expressed in this toxicological profile resides with ATSDR.
*Legislative Background
The toxicological profiles are developed under the Comprehensive Environmental Response,
Compensation, and Liability Act of 1980, as amended (CERCLA or Superfund). CERCLA section
104(i)(1) directs the Administrator of ATSDR to “…effectuate and implement the health related
authorities” of the statute. This includes the preparation of toxicological profiles for hazardous
substances most commonly found at facilities on the CERCLA National Priorities List (NPL) and
that pose the most significant potential threat to human health, as determined by ATSDR and the
EPA. Section 104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a
toxicological profile for each substance on the list. In addition, ATSDR has the authority to prepare
toxicological profiles for substances not found at sites on the NPL, in an effort to “…establish and
maintain inventory of literature, research, and studies on the health effects of toxic substances” under
CERCLA Section 104(i)(1)(B), to respond to requests for consultation under section 104(i)(4), and
as otherwise necessary to support the site-specific response actions conducted by ATSDR.
GLYPHOSATE V
VERSION HISTORY
Date Description
August 2020 Final toxicological profile released
REVIEWERS
PEER REVIEWERS
2. David A. Eastmond, Ph.D., Professor and Toxicologist, Department of Molecular Cell and
Systems Biology, University of California, Riverside, Riverside, California
These experts collectively have knowledge of toxicology, chemistry, and/or health effects. All reviewers
were selected in conformity with Section 104(I)(13) of the Comprehensive Environmental Response,
Compensation, and Liability Act, as amended.
GLYPHOSATE VII
Peer reviewers for subsequent revision to Section 2.19 (Cancer) and Appendix A (MRL Worksheets) in
the Toxicological Profile for Glyphosate were:
2. David A. Eastmond, Ph.D., Professor and Toxicologist, Department of Molecular Cell and
Systems Biology, University of California, Riverside, Riverside, California
3. Paul J. Mills, Ph.D., Professor of Family Medicine and Public Health, University of California,
San Diego
ATSDR scientists review peer reviewers’ comments and determine whether changes will be made to the
profile based on comments. The peer reviewers’ comments and responses to these comments are part of
the administrative record for this compound.
The listing of peer reviewers should not be understood to imply their approval of the profile's final
content. The responsibility for the content of this profile lies with ATSDR.
GLYPHOSATE X
CONTENTS
DISCLAIMER…………….. ....................................................................................................................................... II
FOREWORD…. ..........................................................................................................................................................III
VERSION HISTORY..................................................................................................................................................VI
CONTRIBUTORS & REVIEWERS ......................................................................................................................... VII
CONTENTS…… ......................................................................................................................................................VIII
LIST OF FIGURES .....................................................................................................................................................XI
LIST OF TABLES......................................................................................................................................................XII
CHAPTER 1. RELEVANCE TO PUBLIC HEALTH.................................................................................................1
1.1 OVERVIEW AND U.S. EXPOSURES .....................................................................................................1
1.2 SUMMARY OF HEALTH EFFECTS ......................................................................................................3
1.3 MINIMAL RISK LEVELS (MRLs) ..........................................................................................................7
CHAPTER 2. HEALTH EFFECTS ........................................................................................................................... 10
2.1 INTRODUCTION ................................................................................................................................... 10
2.2 DEATH .................................................................................................................................................... 47
2.3 BODY WEIGHT ..................................................................................................................................... 47
2.4 RESPIRATORY ...................................................................................................................................... 49
2.5 CARDIOVASCULAR ............................................................................................................................. 61
2.6 GASTROINTESTINAL .......................................................................................................................... 62
2.7 HEMATOLOGICAL ............................................................................................................................... 64
2.8 MUSCULOSKELETAL .......................................................................................................................... 64
2.9 HEPATIC................................................................................................................................................. 64
2.10 RENAL .................................................................................................................................................... 67
2.11 DERMAL................................................................................................................................................. 69
2.12 OCULAR ................................................................................................................................................. 69
2.13 ENDOCRINE .......................................................................................................................................... 70
2.14 IMMUNOLOGICAL ............................................................................................................................... 72
2.15 NEUROLOGICAL .................................................................................................................................. 72
2.16 REPRODUCTIVE ................................................................................................................................... 74
2.17 DEVELOPMENTAL ............................................................................................................................... 77
2.18 OTHER NONCANCER .......................................................................................................................... 80
2.19 CANCER ................................................................................................................................................. 80
2.20 GENOTOXICITY.................................................................................................................................. 128
2.21 MECHANISMS OF ACTION ............................................................................................................... 139
CHAPTER 3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL
INTERACTIONS ........................................................................................................................... 144
3.1 TOXICOKINETICS .............................................................................................................................. 144
3.1.1 Absorption ...................................................................................................................................... 144
3.1.1.1 Inhalation Exposure ................................................................................................................... 144
3.1.1.2 Oral Exposure ............................................................................................................................ 144
3.1.1.3 Dermal Exposure ....................................................................................................................... 145
3.1.2 Distribution ..................................................................................................................................... 146
3.1.2.1 Inhalation Exposure ................................................................................................................... 146
3.1.2.2 Oral Exposure ............................................................................................................................ 146
3.1.2.3 Dermal Exposure ....................................................................................................................... 147
3.1.2.4 Other Routes of Exposure .......................................................................................................... 148
3.1.3 Metabolism ..................................................................................................................................... 148
3.1.4 Excretion ......................................................................................................................................... 150
3.1.4.1 Inhalation Exposure ................................................................................................................... 150
3.1.4.2 Oral Exposure ............................................................................................................................ 150
3.1.4.3 Dermal Exposure ....................................................................................................................... 151
3.1.4.4 Other Routes of Exposure .......................................................................................................... 151
3.1.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ....................... 152
3.1.6 Animal-to-Human Extrapolations ................................................................................................... 152
GLYPHOSATE X
3.2 CHILDREN AND OTHER POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ............... 152
3.3 BIOMARKERS OF EXPOSURE AND EFFECT ................................................................................. 153
3.3.1 Biomarkers of Exposure ................................................................................................................. 154
3.3.2 Biomarkers of Effect ....................................................................................................................... 154
3.4 INTERACTIONS WITH OTHER CHEMICALS ................................................................................. 154
CHAPTER 4. CHEMICAL AND PHYSICAL INFORMATION ........................................................................... 156
4.1 CHEMICAL IDENTITY ....................................................................................................................... 156
4.2 PHYSICAL AND CHEMICAL PROPERTIES .................................................................................... 156
CHAPTER 5. POTENTIAL FOR HUMAN EXPOSURE ...................................................................................... 159
5.1 OVERVIEW .......................................................................................................................................... 159
5.2 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL ............................................................ 159
5.2.1 Production ....................................................................................................................................... 159
5.2.2 Import/Export ................................................................................................................................. 163
5.2.3 Use .................................................................................................................................................. 163
5.2.4 Disposal .......................................................................................................................................... 166
5.3 RELEASES TO THE ENVIRONMENT ............................................................................................... 167
5.3.1 Air ................................................................................................................................................... 167
5.3.2 Water .............................................................................................................................................. 168
5.3.3 Soil .................................................................................................................................................. 169
5.4 ENVIRONMENTAL FATE .................................................................................................................. 170
5.4.1 Transport and Partitioning .............................................................................................................. 171
5.4.2 Transformation and Degradation .................................................................................................... 174
5.5 LEVELS IN THE ENVIRONMENT..................................................................................................... 181
5.5.1 Air ................................................................................................................................................... 183
5.5.2 Water .............................................................................................................................................. 184
5.5.3 Sediment and Soil ........................................................................................................................... 184
5.5.4 Other Media .................................................................................................................................... 184
5.6 GENERAL POPULATION EXPOSURE ............................................................................................. 194
5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES .......................................................... 200
CHAPTER 6. ADEQUACY OF THE DATABASE ............................................................................................... 201
6.1 Information on Health Effects................................................................................................................ 201
6.2 Identification of Data Needs .................................................................................................................. 204
6.3 Ongoing Studies ..................................................................................................................................... 208
CHAPTER 7. REGULATIONS AND GUIDELINES ............................................................................................ 210
CHAPTER 8. REFERENCES ................................................................................................................................. 212
APPENDICES
APPENDIX A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS......................................... A-1
APPENDIX B. LITERATURE SEARCH FRAMEWORK FOR GLYPHOSATE ................................ B-1
APPENDIX C. USER’S GUIDE ............................................................................................................. C-1
APPENDIX D. QUICK REFERENCE FOR HEALTH CARE PROVIDERS ....................................... D-1
APPENDIX E. GLOSSARY ................................................................................................................... E-1
APPENDIX F. ACRONYMS, ABBREVIATIONS, AND SYMBOLS .................................................. F-1
GLYPHOSATE XI
LIST OF FIGURES
1-1. Noncancer Health Effects Found in Animals Following Oral Exposure to Glyphosate Technical................. 4
1-2. Summary of Sensitive Targets of Glyphosate Technical – Oral ..................................................................... 8
1-3. Overview of the Number of Animal Studies Examining Glyphosate Technical Health................................ 16
2-2. Overview of the Number of Studies Examining Glyphosate Formulations Health Effects* .. ......................17
2-3. Levels of Significant Exposure to Glyphosate Technical – Oral .................................................................. 29
2-4. Risk of non-Hodgkin’s Lymphoma Relative to Self-Reported Glyphosate Use or Exposure.................... 116
2-5. Risk of Multiple Myeloma Relative to Self-Reported Glyphosate Use or Exposure .................................. 117
3-1. Chemical Structures of Glyphosate and Aminomethylphosphonic Acid (AMPA)..................................... 148
5-1. Agricultural Application Trends of Glyphosate in the United States According to U.S.
Geological Survey (USGS) Data ......................................................................................................................... 165
5-2. Degradation of Glyphosate Under Aerobic Conditions .............................................................................. 174
6-1. Summary of Existing Health Effects Studies of Animals Orally Exposed to Glyphosate by Endpoint)*...202
6-2. Summary of Existing Health Effects Studies on Glyphosate Formulations (Listed by Endpoint)*........... 203
GLYPHOSATE XII
LIST OF TABLES
1-1. Minimal Risk Levels (MRLs) for Technical Glyphosate ...................................................................... 9
2-1. Description of Selected Glyphosate Formulations ............................................................................. 11
2-2. Levels of Significant Exposure to Glyphosate Technical – Oral........................................................ 18
2-3. Levels of Significant Exposure to Glyphosate Formulations – Oral .................................................. 34
2-4. Levels of Significant Exposure to Glyphosate Technical – Dermal ................................................... 46
2-5. Noncancer Outcomes in Humans Exposed to Glyphosate-Containing Products ............................... 51
2-6. Summary of Meta-Analyses of Results from Studies Examining Possible Association Between
Self-Reported Use of Glyphosate and Lymphohematopoietic Cancers ...................................................... 82
2-7. Cancer Outcomes for Solid Tumor-Types in Humans Exposed to Glyphosate-Containing
Products ...................................................................................................................................................... 87
2-8. Lymphohematopoietic Cancer Outcomes in Humans Exposed to Glyphosate-Containing
Products .................................................................................................................................................... 101
2-9. Incidences of Selected Tumors in Sprague-Dawley Rats Administered Technical Glyphosate
(98.7% purity) in the Diet for up to 26 Months ........................................................................................ 119
2-10. Incidences of Selected Tumors in Albino Sprague-Dawley Rats Administered Technical
Glyphosate (96.5% Purity) in the Diet for 2 Years ................................................................................... 120
2-11. Incidences of Renal Tubular Cell Tumors in Male CD-1 Mice Administered Technical
Glyphosate (99.78% Purity) in the Diet for up to 24 Months ................................................................... 123
2-12. Incidences of Tumors in Male and Female CD-1 Mice Administered Glyphosate (≥97.5%
Purity) in the Diet for up to 104 Weeks .................................................................................................... 123
2-13. Carcinogenicity Classification ........................................................................................................ 126
2-14. Genotoxicity of Glyphosate Technical In Vitro.............................................................................. 128
2-15. Genotoxicity of Glyphosate Technical In Vivo .............................................................................. 130
2-16. Genotoxicity of Glyphosate Formulations In Vitro ........................................................................ 130
2-17. Genotoxicity of Glyphosate Formulations In Vivo ......................................................................... 132
4-1. Chemical Identity of Glyphosate and Glyphosate Isopropylaminea ................................................. 157
4-2. Physical and Chemical Properties of Glyphosate and its Isopropylamine Salta ............................... 158
5-1. Glyphosate Salts ............................................................................................................................... 160
5-2. Companies Manufacturing Products Under Pesticide Code 417300 (Glyphosate) .......................... 161
5-3. Glyphosate AI (Pounds) Usage Trends from 1990 to 2014.............................................................. 166
5-4. Lowest Limit of Detection Based on Standards ............................................................................... 182
5-5. Summary of Environmental Levels of Glyphosate .......................................................................... 182
5-6. Outdoor Air Monitoring Data for Glyphosate .................................................................................. 183
GLYPHOSATE XIII
5-7. Glyphosate and its Degradation Products in Water Samples in Major U.S. River Basins ............... 184
5-8. Surface Water Monitoring Data for Glyphosate ............................................................................... 186
5-9. Groundwater Monitoring Data for Glyphosate................................................................................. 189
5-10. Sediment and Soil Monitoring Data for Glyphosate ...................................................................... 191
5-11. Available Glyphosate Human Monitoring Data ............................................................................. 196
6-1. Ongoing Studies on Glyphosate ....................................................................................................... 209
7-1. Regulations and Guidelines Applicable to Glyphosate .................................................................... 210
GLYPHOSATE 1
Glyphosate is a phosphonoglycine non-selective herbicide, first registered for use by the EPA in 1974.
Glyphosate is typically manufactured for commercial use as a salt available in soluble liquid and granule
formulations. Herbicide formulations employing glyphosate salts are commonly produced in
combination with additives, inert ingredients, and surfactants. The salt derivatives enhance absorption of
glyphosate from the surface of the plant or leaf structure, but are not the herbicidally active portion of the
compound. Specific formulations vary in composition and are marketed under numerous trade names
(NPIRS 2017; PAN 2009). Commercial products containing glyphosate may have concentrations ranging
from 0.96 to 94 w/w%. For example, the common herbicide, Roundup®, has product formulations
containing glyphosate in concentrations ranging from 0.96% to as much as 71% (w/w) (NPIRS 2017;
PAN 2016b).
Glyphosate is the active ingredient in a variety of broad spectrum herbicidal products for residential,
commercial, and agricultural purposes. Selected agricultural commodities such as roundup-ready corn
and soybeans have been genetically modified to be resistant to damage when glyphosate is applied to
control undesirable weeds. Glyphosate is produced commercially in the United States as a technical-
grade substance (glyphosate technical) with a purity of ≥80%, though the purity is usually >90% (IPCS
1994, McBean 2011). In 2007, U.S. agricultural use of glyphosate was approximately 82,800 tons and
non-agricultural use of glyphosate was approximately 9,300 tons (Battaglin et al. 2014). For the purposes
of this Profile, the phrase “non-agricultural use” refers to the use of glyphosate outside of agriculture or
farmland, such as to control weeds on a roadside, in a garden, or other use by homeowners.. In 2014, U.S.
agricultural use of glyphosate was approximately 124,953 tons and non-agricultural use of glyphosate was
approximately 13,260 tons (Benbrook 2016). The manufacture and use of glyphosate has led to its direct
release into the environment (EPA 1993). Once glyphosate enters the environment, it has low potential
for environmental bioavailability and is unlikely to bioaccumulate; the chemical is either degraded by
microbial processes or inactivated by adsorption to soil (Shushkova et al. 2010; Smith and Oehme 1992).
Glyphosate is expected to adsorb to soils under most environmental conditions; therefore, leaching into
groundwater is minimal (Smith and Oehme 1992). Glyphosate may enter surface waters due to its use in
some aquatic environments. Volatilization of glyphosate is not an important fate process based on its low
vapor pressure and ionic nature (Smith and Oehme 1992). Transport in the air after spray applications is
GLYPHOSATE 2
dependent on meteorological conditions; ground and aerial applications can result in spray drift, which
may affect non-target plants (PAN 2009; Yates et al.1978).
The general population may be exposed to glyphosate by dermal contact with consumer products, crops,
foliage, or soils containing residues of this chemical; ingestion of plants, crops, foods, or waters
containing residues of this chemical; and inhalation of mist or spray during the use of products containing
this chemical. As a result of its widespread usage, glyphosate is present at low levels in a wide range of
foods (FAO and WHO 2016). The greatest potential for exposure can be expected for people who use
glyphosate products at home and for populations residing near agricultural areas and crop farms,
manufacturing and processing plants where glyphosate is produced or used, and hazardous waste disposal
sites containing glyphosate.
Occupational exposure of glyphosate may occur via inhalation, dermal contact, and/or ocular contact
during manufacture, transport, use, and disposal. Farmers and home gardeners using herbicides
containing glyphosate may be exposed to glyphosate via inhalation, dermal contact, and/or ocular contact
as well. People may be exposed to glyphosate upon entering areas where it has been recently applied.
Dermal contact appears to be the major route of exposure to glyphosate for people involved in its
application.
Children are expected to be exposed to glyphosate by the same routes as adults in the general population.
Products containing glyphosate should be kept out of the reach of children. Due to increased hand-to-
mouth activity and playing habits, children are more likely to come into contact with glyphosate residues
that may be present in soil. Glyphosate is not likely to bioaccumulate in breast milk (Bus 2015) and was
not detected in breast milk from lactating mothers with detectable glyphosate in their urine (McGuire et
al. 2016). In one small study, neither glyphosate nor its major degradation product,
aminomethylphosphonic acid (AMPA), were detected in the maternal or fetal cord serum of pregnant
subjects (Aris and LeBlanc 2011).
See Chapter 5 for more detailed information regarding concentrations of glyphosate in environmental
media.
GLYPHOSATE 3
Information regarding the toxicity of glyphosate comes primarily from oral studies in laboratory animals
exposed to glyphosate technical. No information was located regarding health effects in humans exposed
to glyphosate technical; human exposures are to herbicides that contain glyphosate and other ingredients or
to glyphosate residues in selected food sources. Human studies have reported possible associations
between glyphosate herbicide use and various health outcomes. A few animal studies evaluated the effects
of inhalation or oral exposure to glyphosate formulations containing surfactant and additional unspecified
substances. Reported effects may be due, at least in part, to the surfactant. Furthermore, glyphosate
formulations vary in specific components and their relative proportions, thus precluding meaningful
comparisons of toxic effect levels. Therefore, Figure 1-1 contains summary information related only to
glyphosate technical.
GLYPHOSATE 4
Figure 1-1. Noncancer Health Effects Found in Animals Following Oral Exposure
to Glyphosate Technical
* Classification of glyphosate used in each study is based on author-report. Technical-grade glyphosate has a purity
of ≥80%, though the purity is usually >90% (IPCS 1994, McBean 2011).
GLYPHOSATE 5
As illustrated in Figure 1-1, gastrointestinal disturbance and effects on the salivary gland appear to be the
most sensitive noncancer effects in animal studies that employed oral exposure to glyphosate technical.
Ocular, hepatic, renal, and body weight effects have been reported as well. Developmental effects were
observed at dose levels resulting in maternal toxicity. Effects observed in animals are considered relevant
to human health in the absence of experimental data to indicate otherwise.
Gastrointestinal Effects. Gastrointestinal symptoms (e.g., nausea, vomiting, abdominal pain, sore throat,
mucosal damage in mouth and esophagus) are commonly reported in patients ingesting glyphosate
products (Chang et al. 1999; Lee et al. 2000, 2008; Moon and Chun 2010; Roberts et al. 2010; Sawada et
al. 1988; Talbot et al. 1991; Tominack et al. 1991). Gastrointestinal effects have frequently been seen in
animal studies. For example, soft stool/diarrhea were reported in pregnant rabbits gavaged with
glyphosate technical during gestation (EPA 1992f, 2017b) and rats administered glyphosate technical in
the diet for 2 generations (EPA 1992a). Inflammation of gastric mucosa was observed in female rats
orally exposed to glyphosate technical for 2 years (EPA 1991a, 1991b). Cytoplasmic alterations were
reported in salivary glands of glyphosate-treated rats and mice; the toxicological significance of these
salivary gland changes is uncertain (NTP 1992).
Body Weight Effects. Depressed body weight was observed during intermediate- and chronic-duration
oral exposure of laboratory animals to glyphosate technical at doses ≥1,183 mg/kg/day (EPA 1985a,
1991a, 1991b, 1992a).
Hepatic Effects. Increased liver weight and increased serum markers of liver effects (alkaline
phosphatase [AP], alanine aminotransferase [ALT], and/or bile acids) were observed in rats administered
glyphosate technical for 13 weeks at ≥1,678 mg/kg/day (NTP 1992). Centrilobular hepatocellular
necrosis was observed in livers from male mice administered glyphosate technical for 2 years at an
estimated dose of 4,945 mg/kg/day (EPA 1985a). Other studies found less conclusive signs of hepatic
effects such as changes in thiobarbituric acid reactive substances (Almeida et al. 2017; Milic et al. 2018)
and significantly increased ROS levels in the liver (Milic et al. 2018).
Renal Effects. Increased specific gravity of urine and decreased urinary pH were noted among male rats
administered glyphosate technical for 2 years at 940 mg/kg/day (EPA 1991a, 1991b). Female mice
administered glyphosate technical for 2 years at 6,069 mg/kg/day exhibited significantly increased
incidence of renal proximal tubule epithelial basophilia and hypertrophy (EPA 2015a).
GLYPHOSATE 6
Ocular Effects. In a report of human case series of 1,513 ocular exposures to glyphosate products, minor
symptoms (primarily transient irritation) were observed in 70% of the cases; most (99%) complained of
eye pain (Acquavella et al. 1999). Lens abnormalities were observed in male rats orally administered
glyphosate technical for 2 years at 940 mg/kg/day (EPA 1991a, 1991b). According to EPA (1993),
glyphosate is considered mildly irritating to the eye following ocular instillation.
Cancer Effects. The carcinogenic potential of glyphosate has been evaluated in six meta-analyses
(Chang and Delzell 2016; IARC 2017; Schinasi and Leon 2014; Leon et al. 2019; Pahwa et al. 2019;
Zhang et al. 2019a) and a number of case-control and cohort epidemiology studies (see Section 2.19 for
detailed information and specific citations). The meta-analyses reported positive associations between
glyphosate use and selected lymphohematopoietic cancers. Most of the case-control and cohort studies
used self-reported ever/never glyphosate use as the biomarker of exposure, and subjects were likely
exposed to other pesticides as well. Numerous studies reported risk ratios greater than 1 for associations
between glyphosate exposure and risk of non-Hodgkin’s lymphoma or multiple myeloma; however, the
reported associations were statistically significant only in a few studies.
• Hematological effects (decreases in red blood cells, hematocrit, and hemoglobin, and increases in
mean corpuscular volume and neutrophils in mice),
• Hepatic effects (increased serum liver enzyme activity and histopathologic liver lesions in male
rats),
• Renal effects (histopathologic kidney lesions in male rats), and
• Reproductive effects (increased percentage of morphologically abnormal sperm in rats).
Animal studies submitted to EPA’s Office of Pesticides Programs to fulfill requirements for the
registration of a particular glyphosate formulation for use in the United States involve exposure to
glyphosate technical (typically >90% purity). Some animal studies in the open literature used glyphosate
formulations that typically included 1–41% glyphosate technical (or glyphosate salts) and up to 18%
surfactant (along with other “inert” ingredients). Surfactants in glyphosate formulations may be at least
partly responsible for the toxic effects from overexposure to glyphosate formulations (Adam et al. 1997;
Sawada et al. 1988; Williams et al. 2000). Human exposure to glyphosate formulations via its use in
weed control includes exposure to all substances in a particular glyphosate formulation. No MRLs were
derived for glyphosate formulations due to the wide variation in glyphosate content and surfactants used
in various glyphosate formulations and the fact that surfactants can contribute to the toxicity of
glyphosate formulations. However, because exposures of the general population via food or water
sources with measurable glyphosate residues most likely involve glyphosate and/or its breakdown
products rather than the intact glyphosate-based formulation, health effects data associated with oral
exposure to glyphosate technical are considered relevant to potential derivation of oral MRLs for
glyphosate. Oral MRLs based on glyphosate technical would not be applicable to intentional or
accidental ingestion of a glyphosate formulation.
Available data for inhalation exposure to glyphosate technical are limited to a summary from a single
4-week repeated-exposure rat study in which no effects were observed at the highest exposure level (EPA
1985c). The inhalation database was, therefore, not considered adequate for derivation of inhalation
MRLs for glyphosate. As presented in Figure 1-1, available data have identified the gastrointestinal tract
GLYPHOSATE 8
as the most sensitive target of glyphosate toxicity following oral exposure. The oral database was
considered adequate for derivation of acute- and chronic-duration oral MRLs for glyphosate. These
MRLs are summarized in Table 1-1 and discussed in detail in Appendix A. The chronic-duration
MRL value is adopted as the intermediate-duration oral MRL for glyphosate (see Appendix A).
As illustrated in Figure 1-2, gastrointestinal disturbances (e.g., loose stools/diarrhea, decreased fecal
production, inflammation of gastric mucosa, cytoplasmic alterations in salivary glands) appear to be
the most sensitive effects of glyphosate technical toxicity in animals. The lowest-observed-adverse-
effect levels (LOAELs) in Figure 1-2 reflect actual doses (levels of exposure) employed in animal
studies.
2.1 INTRODUCTION
The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and
other interested individuals and groups with an overall perspective on the toxicology of glyphosate. It
contains descriptions and evaluations of toxicological studies and epidemiological investigations and
provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health.
When available, mechanisms of action are discussed along with the health effects data; toxicokinetic
mechanistic data are discussed in Section 3.1.
A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile.
To help public health professionals and others address the needs of persons living or working near hazardous
waste sites, as well as people exposed during production and/or use of glyphosate-containing products, the
information in this section is organized by health effect. These data are discussed in terms of route of
exposure (inhalation, oral, and dermal) and three exposure periods: acute (≤14 days), intermediate (15–
364 days), and chronic (≥365 days).
As discussed in Appendix B, a literature search was conducted to identify relevant studies examining health
effect endpoints. Figure 2-1 for glyphosate technical and Figure 2-2 for glyphosate formulations provide an
overview of the database of studies in humans or experimental animals included in this chapter of the profile.
These studies evaluate the potential health effects associated with inhalation, oral, or dermal exposure to
glyphosate, but may not be inclusive of the entire body of literature.
This ATSDR Toxicological Profile for Glyphosate includes data for glyphosate technical (purity typically
>90%) and glyphosate formulations (typically 1–41% v/v glyphosate technical or glyphosate salts and
≤18% polyoxyethyleneamine [POEA] surfactant). Surfactants in glyphosate formulations may be at least
partly responsible for the toxic effects from exposure to glyphosate formulations (Adam et al. 1997;
Sawada et al. 1988; Williams et al. 2000; Mesnage et al. 2013). As such, health effects observed in
studies of animals exposed to relatively high levels of glyphosate technical may not accurately reflect
health effects from human exposure to glyphosate formulations during application as an herbicide.
However, because the general population may be exposed to glyphosate and/or its breakdown products
(rather than to a particular glyphosate formulation) in selected food sources or contaminated drinking
GLYPHOSATE 11
2. HEALTH EFFECTS
water, health effects from animal studies in which glyphosate technical was used as a test substance are
considered relevant to human health.
Product names and reported descriptions for glyphosate-containing products included in this toxicological
profile are summarized in Table 2-1 by reference (alphabetical order). Hereafter, each glyphosate-
containing formulation will generally be identified only by the reported product name.
2. HEALTH EFFECTS
Animal oral study information for glyphosate technical is presented in Table 2-2 and Figure 2-3. Animal
oral study information for glyphosate formulations is presented in Table 2-3. Animal dermal study
information for glyphosate technical is presented in Table 2-4.
Levels of significant exposure (LSEs) for each route and duration are presented in tables and illustrated in
figures. LSE tables and figures for animal inhalation studies of glyphosate technical and glyphosate
formulations are precluded by lack of data. The points in the figures showing no-observed-adverse-effect
levels (NOAELs) or lowest-observed-adverse-effect levels (LOAELs) reflect the actual doses (levels of
exposure) used in the studies. LOAELs have been classified into "less serious" or "serious" effects.
"Serious" effects are those that evoke failure in a biological system and can lead to morbidity or mortality
(e.g., acute respiratory distress or death). "Less serious" effects are those that are not expected to cause
significant dysfunction or death, or those whose significance to the organism is not entirely clear.
GLYPHOSATE 13
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ATSDR acknowledges that a considerable amount of judgment may be required in establishing whether
an endpoint should be classified as a NOAEL, "less serious" LOAEL, or "serious" LOAEL, and that in
some cases, there will be insufficient data to decide whether the effect is indicative of significant
dysfunction. However, the Agency has established guidelines and policies that are used to classify these
endpoints. ATSDR believes that there is sufficient merit in this approach to warrant an attempt at
distinguishing between "less serious" and "serious" effects. The distinction between "less serious" effects
and "serious" effects is considered to be important because it helps the users of the profiles to identify
levels of exposure at which major health effects start to appear. LOAELs or NOAELs should also help in
determining whether or not the effects vary with dose and/or duration, and place into perspective the
possible significance of these effects to human health.
A User's Guide has been provided at the end of this profile (see Appendix C). This guide should aid in
the interpretation of the tables and figures for LSEs and MRLs.
Glyphosate-containing products are among the most widely-used herbicides in commercial, agricultural,
and residential settings (NPIC 2015). Selected field crops have been genetically modified to resist
damage from glyphosate; such crops can be sprayed with glyphosate formulations to control weed growth
without harming the genetically-modified plants. Selected glyphosate-containing products are labeled for
use as desiccants on some grain crops a few weeks prior to harvest.
Glyphosate technical (purity typically >90%) has been evaluated in numerous animal studies, most of
which employed the oral exposure route and were submitted to EPA’s Office of Pesticide Programs
through the pesticide registration program as directed by the Federal Insecticide, Fungicide, and
Rodenticide Act (FIFRA), Federal Food, Drug and Cosmetic Act (FFDCA), and Food Quality Protection
Act (FQPA). The submitted studies are generally unpublished proprietary studies. EPA evaluated
submitted study reports and produced summaries termed Data Evaluation Records or Data Evaluation
Reports (DERs) that include study details and EPA’s own conclusions regarding study design, results,
and conclusions of the study authors. Information from DERs received from EPA is summarized in this
ATSDR Toxicological Profile for Glyphosate (note: selected DERs can be requested at:
https://www.epa.gov/foia or viewed from a list of cleared reviews for glyphosate or glyphosate salts at
https://archive.epa.gov/pesticides/chemicalsearch/chemical/foia/web/html/a.html). EPA evaluated and
produced DERs for selected proprietary animal studies submitted by various chemical companies to
agencies or organizations outside the United States for product registration purposes. Results from the
DERs available to ATSDR were included in the Toxicological Profile for Glyphosate.
GLYPHOSATE 14
2. HEALTH EFFECTS
Epidemiological studies of glyphosate are predominantly case-control and cohort studies that examined
possible associations between exposure to glyphosate (in glyphosate-containing herbicides) and selected
health outcomes (noncancer and cancer endpoints), or case reports following accidental or intentional
ingestion of glyphosate-containing products. These epidemiology studies are summarized in Table 2-5
(noncancer) and Table 2-7 (cancer). The majority of the studies used self-reported (or proxy reported)
ever/never glyphosate use as the measure of exposure and some studies included a metric for frequency of
exposure. There is no information regarding health effects in humans exposed to glyphosate technical.
Most reliable dose-response health effects data come from oral studies of animals administered
glyphosate technical (seeFigure 2-1 for an overview of the number of animal studies examining potential
endpoints of concern from oral exposure to glyphosate technical). No information was located regarding
the effects of inhaled glyphosate technical. In a 4-week study that employed repeated inhalation exposure
of rats to Roundup®, no adverse effects were observed at the highest exposure concentration tested
(360 mg Roundup®/m3) (EPA 1985c). Limited animal data for dermal exposure to glyphosate technical
indicate that glyphosate is not a dermal irritant. Results from the oral animal studies identify the
following targets of glyphosate toxicity, albeit at relatively high dose levels:
• Body weight effects: Depressed body weight and/or depressed body weight gain resulted from
repeated dosing of glyphosate technical at dose levels ≥1,183 mg/kg/day.
• Hepatic effects: Increases in liver weight and serum ALT activity were observed in one
repeated-dose study at a dose level of 1,678 mg/kg/day.
• Ocular effects: Lens abnormalities were observed in one repeated-dose study at a dose level of
940 mg/kg/day.
• Renal effects: Indicators of renal toxicity were noted in rats and mice administered glyphosate
technical in the diet for 2 years at high doses (940 and 6,069 mg/kg/day, respectively).
2. HEALTH EFFECTS
An overview of the number of human and animal studies examining potential endpoints of concern from
exposure to glyphosate formulations is presented inFigure 2-2. Results from available animal studies
identify the following targets of toxicity:
• Endocrine effects: Decreased serum testosterone was noted in male rat weanlings administered
a glyphosate formulation orally at 5 mg/kg/day.
• Body weight effects: Seriously depressed body weight gain was observed in mice administered a
glyphosate formulation orally at 50 mg/kg/day.
• Renal effects: Histopathologic kidney lesions were noted in male rats gavaged once with a
glyphosate formulation at 250 mg/kg.
• Hepatic effects: Increased serum liver enzyme activity and histopathologic liver lesions were
reported in male rats repeatedly gavaged with a glyphosate formulation at 487 mg/kg/day.
• Hematological effects: Decreases in red blood cells, hematocrit, and hemoglobin, and increases
in mean corpuscular volume and neutrophils were reported in mice administered a glyphosate
formulation orally at 500 mg/kg/day.
2. HEALTH EFFECTS
Figure 2-1. Overview of the Number of Animal Studies Examining Glyphosate Technical Health Effects*
Most studies examined the potential body weight, gastrointestinal, hematological, hepatic, and developmental effects of
glyphosate technical (counts represent studies examining endpoint)
Death 3
Body weight 20 Exposure Route Studies
Respiratory -
Dermal
Cardiovascular - 3%
Gastrointestinal 11
Hematological 8 Oral
97%
Musculoskeletal -
Hepatic 9
Renal 8
Dermal 1
Exposure Duration Studied
Ocular 4
Endocrine 1 Chronic Acute
20% 27%
Immunological 1
Neurological 5
Reproductive 5 Intermediate
53%
Developmental 10
Other Noncancer -
Cancer 7
*Includes only animal studies that employed oral exposure to glyphosate technical as discussed in Chapter 2. A total of 30 studies include those finding no effect.
Most studies examined multiple endpoints.
GLYPHOSATE 17
2. HEALTH EFFECTS
Figure 2-2. Overview of the Number of Studies Examining Glyphosate Formulations Health Effects*
Most epidemiological studies examined potential cancer, respiratory, and developmental effects associated with
glyphosate-containing products; most animal studies examined potential body weight and developmental effects
associated with glyphosate-containing products
More studies evaluated health effects in humans than animals (counts represent studies examining endpoint)
Hepatic 8 1
Renal 5 4
Dermal - 6
Ocular 1 2 Exposure Duration Studied
Endocrine 7 3 Chronic
13% Acute
Immunological 1 - 29%
Neurological 8 3
Intermediate
Reproductive 13 3 58%
Developmental 9 7
Other Noncancer - 6
Cancer - 22
*A total of 85 studies, including those finding no effect. Many studies examined multiple endpoints. Reliable exposure route and duration information was not
typically available for humans. Therefore, relative exposure route and duration proportions are plotted only for animal studies.
GLYPHOSATE 18
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aPurities reported in this table are the information provided by the study authors in the study methodologies regarding the chemical used in the experiments.
bThe number corresponds to entries in Figure 2-3; differences in levels of health effects and cancer effects between male and females are not indicated in
Figure 2-3. Where such differences exist, only the levels of effect for the most sensitive gender are presented.
cUsed to derive an acute-duration oral MRL for glyphosate; NOAEL divided by an uncertainty factor of 100 (10 for animal to human extrapolation and 10 for human
variability); see Appendix A for more detailed information regarding the MRL.
dUsed to derive a chronic-duration oral MRL for glyphosate; NOAEL divided by an uncertainty factor of 100 (10 for animal to human extrapolation and 10 for
human variability); see Appendix A for more detailed information regarding the MRL.
ALT = alanine aminotransferase; AP = alkaline phosphatase; BC = biochemistry; BW or Bd Wt = body weight; C = capsule; CS = clinical signs;
Develop = developmental; DX = developmental toxicity; EA = enzyme activity; (F) = exposure in feed; F = female(s); FI = food intake; FX = fetal toxicity;
G = gavage, neat; Gastro = gastrointestinal; GD = gestation day; GN = gross necropsy; GW = gavage in water vehicle; HE = hematology;
Hemato = hematological; HP = histopathology; Immuno = immunological; LD 50 = lethal dose, 50% kill; LE = lethality; LOAEL = lowest-observed-adverse-effect
level; M = male(s); MRL = Minimal Risk Level; MX = maternal toxicity; NOAEL = no observed-adverse-effect level; NS = not specified; OF = organ function;
OP = ophthalmology; OW = organ weight; Repro = reproductive; TG = teratogenicity; UR = urinalysis; WI = water intake
GLYPHOSATE 29
2. HEALTH EFFECTS
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Repro 1.75 M
GLYPHOSATE 41
2. HEALTH EFFECTS
MOUSE 15 days 0, 50, 500 BW, EA, HE, Bd wt 50 60–66% depressed mean body
(albino 1 time/day HP, OF weight gain
Swiss) 10 (GW)
M, 10 F
Hemato 50 500 Decreased red blood cells,
hematocrit, hemoglobin; increased
mean corpuscular volume,
neutrophils
Hepatic 500
Jasper et al. 2012 – Glyphosate Formulation – Roundup® Original (41% glyphosate and 16% POEA
GLYPHOSATE 42
2. HEALTH EFFECTS
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2. HEALTH EFFECTS
Develop 420 M
Teleken et al. 2019 – Glyphosate formulation – Roundup® Original (Monsanto, Brazil, not otherwise described)
MOUSE Daily 0, 250, 500 BW IX NX Bd wt 250 M significant reduced body weight gain
(Swiss) 6M 12 weeks OW (33%) after 90 days, decreased
(G) grooming time
Resp 250 M 50% decrease in relative lung weight
Hepatic 250 M 44% decrease in relative liver weight
Renal 250 M 50% decrease in relative kidney
weight
Neuro 250 M decreased locomotor activity,
increased anxiety-like behavior and
anxiety index (p<0.001) compared to
control
Ait Bali et al. 2017 – Glyphosate formulation – Roundup® (glyphosate concentration 360 g/L in the form of glyphosate isopropylamine salt 486
g/L)
MOUSE Daily 0, 250, 500 GN NX Gastro 250 M decrease in total bacterial count in
(Swiss) 6M 12 weeks gut (p<0.001) compared to control
(G)
Neuro 250 M increase in anxiety index (p<0.01)
and decreased grooming time
(p<0.001) compared to controls
Aitbali et al. 2018 – Glyphosate formulation – Roundup® (glyphosate concentration 360 g/L in the form of glyphosate isopropylamine salt 486
g/L)
GLYPHOSATE 45
2. HEALTH EFFECTS
a Purities reported in this table are the information provided by the study authors in the study methodologies regarding the chemical used in the experiments.
Bd Wt or BW = body weight; CS = clinical signs; Develop = developmental; DX = developmental toxicity; EA = enzyme activity; Endocr = endocrine; F = female(s);
FI = food intake; FX = fetal toxicity; Gastro = gastrointestinal; GD = gestation day; GN = gross necropsy; GW = gavage in water vehicle; HE = hematology; Hemato
= hematological; HP = histopathology; IT = intratracheal; LE = lethality; LOAEL = lowest-observed-adverse-effect level; M = male(s); MX = maternal toxicity;
NOAEL = no observed-adverse-effect level; NS = not specified; OF = organ function; OW = organ weight; POEA = polyoxyethyleneamine; PPD = post-parturition
day; Repro = reproductive; TG = teratogenicity; W = water vehicle; WI = water intake
GLYPHOSATE 46
2. HEALTH EFFECTS
Less
Species (strain) Exposure Doses Parameters serious Serious
No./group parameters (mg/kg/day) monitored Endpoint NOAEL LOAEL LOAEL Effect
INTERMEDIATE EXPOSURE
Rabbit (New 21 days, 0, 100, BC, BW, Bd Wt 5,000
Zealand) 5 days/week, 1,000, CS, EA, FI, Hemato 5,000
10 M, 10 F 6 hours/day 5,000 GN, HE,
HP, LE, OW Hepatic 5,000
Dermal 1,000 5,000 Very slight erythema and edema at
application site
EPA 1992c – glyphosate technical, purity not specified
a Purities reported in this table are the information provided by the study authors in the study methodologies regarding the chemical used in the experiments.
BC = biochemistry; BW or Bd wt = body weight; CS = clinical signs; EA = enzyme activity; F = female(s); FI = food intake; GN = gross necropsy;
HE = hematology; Hemato = hematological; HP = histopathology; LE = lethality; LOAEL = lowest-observed-adverse-effect level; M = male(s); NOAEL = no
observed-adverse-effect level; OW = organ weight
GLYPHOSATE 47
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2.2 DEATH
Several case report series have reported deaths in individuals intentionally ingesting glyphosate products
(Chen et al. 2009; Kim et al. 2014; Moon et al. 2018; Roberts et al. 2010; Sawada et al. 1988; Talbot et al.
1991; Tominack et al. 1991). The predominant cause of death was often shock (hypovolemic or
cardiogenic), hypotension, and respiratory failure, often due to aspiration (Chen et al. 2009; Kim et al.
2014; Moon et al. 2018; Talbot et al. 1991). Among 107 patients who ingested glyphosate isopropylamine
salt, eleven fatalities were reported (10.3% rate) while none were observed in the glyphosate ammonium
salt group, for which there were 40 patients (Moon et al. 2018). A retrospective cohort study reported that
14 of 150 patients with glyphosate surfactant herbicide poisoning died and that nonsurviving patients
were statistically older compared to surviving patients (Cho et al. 2019).
An acute oral LD50 value of 4,320 mg/kg/day was reported following single oral dosing of rats with
glyphosate technical (EPA 1992b). In a developmental toxicity study, 6/25 pregnant rats died during oral
dosing of glyphosate technical at 3,500 mg/kg/day; there were no deaths during treatment at
1,000 mg/kg/day (EPA 1992e). No adequate sources were located regarding death in laboratory animals
exposed to glyphosate technical by inhalation or dermal routes.
In a study of female Wistar rats exposed to 126 or 315 mg/kg/day of a glyphosate formulation for 60
days, 6/12 rats died (Hamdaoui et al. 2018). In a study that employed oral dosing of pregnant rats with
Roundup®, 8/15 dams died during the first 8 days of treatment at 1,000 mg/kg/day glyphosate
(Dallegrave et al. 2003). No deaths occurred in a 4-week study of rats intermittently exposed to
Roundup® at exposure levels as high as 360 mg/m3 (approximately 36 mg Roundup®/m3) (EPA 1985c).
No adequate sources were located regarding death in laboratory animals exposed to glyphosate
formulations by the dermal route.
Oral exposure of rats to glyphosate technical at relatively high doses resulted in significant effects on
body weight and/or body weight gain. Pregnant rats gavaged at 3,500 mg/kg/day during GDs 6–19
exhibited as much as 28.5% lower mean body weight gain than controls (EPA 1992e). Body weight gain
was 12–18% less than that of controls in two generations of parental male and female rats exposed via the
diet for 14–19 weeks at 2,219 or 3,134 mg/kg/day, respectively (EPA 1992a). No treatment-related effects
on body weight were seen among young female mice treated for 28 days at estimated doses up to
1,447.5 mg/kg/day (EPA 2013b). In 13-week oral studies, body weight and/or body weight gain among
GLYPHOSATE 48
2. HEALTH EFFECTS
rats and mice at oral doses in the range of 2,273–11,977 mg/kg/day were 10–18% less than controls (NTP
1992). In a 2-year study, female rats dosed at 1,183 mg/kg/day exhibited 13% lower mean body weight
than controls at treatment week 81 (EPA 1991a).
Evidence of treatment-related effects on body weight among laboratory animals receiving lower oral
doses of glyphosate or glyphosate-based herbicides varied by study. Studies using doses of glyphosate
technical at ≤1,000 mg/kg/day during acute-, intermediate-, or chronic-duration exposure found no effects
on body weight (Baier et al. 2017; El-Shenawy 2009; EPA 1986a, 1987, 1991a, 1991b, 1992a, 1992d,
1992e, 1992f, 1992g, 2013a, 2013b, 2017b; Manservisi et al. 2019). In contrast, body weight changes
were sometimes observed in lower dose oral studies using glyphosate formulations (Ait Bali et al. 2017;
Almeida et al. 2017; Cattani et al. 2017; Hamdaoui 2018; Pandey et al. 2019; Teleken et al. 2019).
Several studies evaluated effects of oral exposure to glyphosate formulations on body weight. Limited
results indicate that mice may be more sensitive than rats to body weight effects from repeated oral
exposure to glyphosate formulations. In intermediate studies on male mice, significantly reduced body
weight gain (>70%) occurred at 250 mg/kg/day after 6-12 week exposure (Ait Bali et al. 2017), and in
offspring exposed in utero, during lactation and then orally from post-natal day 21 to 60 (14% less than
controls) (Cattani et al. 2017). However, in another intermediate oral study, pregnant C57B1/6 mice
showed a 17% decrease in body weight and an approximate 25% decrease in body weight gain, while
their male offspring exposed in utero and during lactation did not have significantly different body weight
or body weight gain when compared with controls (Teleken et al. 2019). Seriously-depressed mean body
weight gain (60–66% less than controls) was reported for albino Swiss mice gavaged with Roundup
Original® at 50 mg/kg/day for 15 days and approximately 10% body weight loss for mice dosed at 500
mg/kg/day (Jasper et al. 2012). When compared to controls, male rats orally exposed to a range of
concentrations of Roundup® for two weeks showed an estimated 37% decrease in body weight when
exposed to 100 mg/kg/day and an estimated 33% decrease in body weight when exposed to 250
mg/kg/day. Pregnant rats fed 500 mg/kg/day Roundup® via gavage for 7 days had 10% less body weight
gain compared to controls, when exposed simultaneously with paraquat (Almeida et al. 2017). In rats, 8-
10% less body weight gain was seen after exposure to 126 mg/kg/day in feed for 60 days (Hamdaoui
2018).
However, other studies found no effects of oral glyphosate exposure on body weight. No significant
effects on body weight were observed among Wistar rats gavaged with Roundup® at 56 or 560
mg/kg/day for up to 13 weeks (Caglar and Kolankaya 2008), male mice orally exposed to Roundup® for
GLYPHOSATE 49
2. HEALTH EFFECTS
35 days (Jiang et al. 2018). pregnant Wistar rats gavaged with Roundup® at 1,000 mg/kg/day during
GDs 6–15 (Dallegrave et al. 2003), or maternal Wistar rats gavaged with Roundup® at 50–
450 mg/kg/day during gestation and lactation (Dallegrave et al. 2007). No effects on body weight were
observed among male Wistar rats gavaged with Roundup Transorb® at 250 mg/kg/day during postnatal
days (PNDs) 23–53 (Romano et al. 2010). After exposure to 1.75 mg/kg/day of glyphosate technical or
Roundup® Bioflow during pregnancy and lactation, no weight changes were observed in Sprague-
Dawley F0 females or their male offspring (Manservisi et al. 2019). At higher exposure levels to
glyphosate formulations (3.69 mg/kg/d and 352.2 mg/kg/d) during pregnancy, F0 and F1 female Wistar
rats showed no signs of glyphosate-associated weight changes (Milesi et al. 2018).
Non-oral exposure to glyphosate and glyphosate formulations was not associated with changes in body
weight. No significant body weight effects occurred in a 4-week inhalation study of rats intermittently
exposed to Roundup® at exposure levels as high as 360 mg/m3 (approximately 36 mg Roundup®/m3)
(EPA 1985c). A study on male albino rats intraperitoneally exposed to 269.9 mg/kg/day of Roundup® for
up to two weeks (El-Shenawy 2009) also found no changes in body weight, No significant treatment-
related effects on body weight were observed among rabbits administered repeated dermal applications of
glyphosate technical at doses in the range of 100–5,000 mg/kg/application for 21 days (EPA 1992c).
When mice were acutely exposed subcutaneously to 2 mg/kg/bw, no effects on body weight were seen
(Altamirano et al. 2018; Guerrero Schimpf et al. 2017; Guerrero Schimpf et al. 2018). No effects on body
weight were seen in male mice after intranasal exposure to 50 mg/kg/day for 3 times a week for 4 weeks
(Baier et al. 2017).
2.4 RESPIRATORY
As summarized in Table 2-5, several investigations of the Agricultural Health Study participants have
examined the possible associations between use of glyphosate-containing products and increased risk of
rhinitis, wheezing, atopic asthma, allergic asthma, or chronic bronchitis (Hoppin et al. 2002, 2006a,
2006b, 2007, 2008, 2009; Slager et al. 2009, 2010). No associations were found for diagnosed chronic
bronchitis (Hoppin et al. 2007) or for wheezing after adjusting for confounding exposure to other
pesticides (Hoppin et al. 2002, 2006a, 2006b). Current rhinitis was associated with glyphosate use among
commercial applicators (Slager et al. 2009) and farmers (Slager et al. 2010), but no relationship between
risk and the number of days of use per year was found among the commercial applicators (Slager et al.
2009). The relationship seen in commercial applicators was limited to applicators that also reported using
2,4-D. Applicators using 2,4-D or glyphosate alone did not show an increased risk of rhinitis (Slager et al.
GLYPHOSATE 50
2. HEALTH EFFECTS
2009). An association between glyphosate use and the risk of atopic asthma was found among farm
women, but there was no association with nonatopic asthma (Hoppin et al. 2008). No associations were
found between glyphosate use by male farmers and risk of allergic or nonallergic asthma (Hoppin et al.
2009). An association between glyphosate use and the risk of both allergic and nonallergic wheeze was
found among male farmers, with an increase in risk for allergic wheeze with increasing days of use per
year (Hoppin et al. 2017). It is noted that many of these studies did not account for use of other
pesticides.
A study by Camacho and Mejia (2017) investigated the association between aerial applications of
glyphosate in Colombia and health effects of individuals living in the sprayed areas. The association was
assessed using individual medical record data and information about Colombia’s aerial spraying program.
Several health outcomes including respiratory illnesses was examined and a positive association was
observed. For each additional square kilometer increase in area sprayed with glyphosate there was an
increase in the proportion of respiratory diagnoses 7 to 15 days following exposure.
Respiratory failure or distress was reported in about 10–25% of the cases of intentional ingestion of
glyphosate products (Lee et al. 2000; Moon and Chun 2010; Picetti et al. 2018; Tominack et al. 1991).
Cho et al. (2019) found that the most common complication occurring in patients who had ingested
glyphosate surfactant herbicide was acute respiratory distress syndrome.
GLYPHOSATE 51
2. HEALTH EFFECTS
Respiratory
Camacho and Mejia 2017 Exposure: aerial spraying of glyphosate Increased number of respiratory illnesses
on coca crops and the general population consistent across all specifications analyzed
Cross-sectional study examining individual health living in the spray areas within study period (only statistically significant p values were
records from the general public over a five-year 2003 to 2007 presented).
period (2003 to 2007) merged with data of aerial
spraying events. The study examined the data Regression Adjustments: age, age
under several specifications: square, health regime, municipal tax
• Complete sample set: 39,766,259 income, population, area in square km,
observations rurality index, average monthly rainfall,
• Municipalities with positive aerial municipal spending on education and
spraying: 7,264,691 observations health, subsidized regime coverage, year
• Municipalities with non-immigrant and month dummy
population: 37,736,485 observations
• High and low income municipalities:
20,131,375and 19,634,884 observations,
respectively
Hoppin et al. 2002 Exposure: glyphosate ever use and Wheeze, self-reported
application frequency categories OR 1.05 (0.95–1.17), p=0.04 for trend of
Cohort study of 20,468 participants in the increasing exposure days
Agricultural Health Study in Iowa and North Logistic regression adjustments: age,
Carolina state, smoking history, asthma-atopy
status
Hoppin et al. 2006a Exposure: glyphosate ever use in the Wheeze, self-reported
year prior to enrollment OR 1.05 (0.94–1.17), farmers
GLYPHOSATE 52
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Hoppin et al. 2006b Exposure: glyphosate ever use in the Wheeze, self-reported
year prior to enrollment OR 1.38 (1.03–1.86)
Cohort study of 2,255 commercial pesticide OR 1.14 (0.83–1.57), with adjustment for
applicators participating in the Agricultural Health Logistic regression adjustments: age, use of chlorimuron-ethyl pesticide
Study in Iowa and North Carolina smoking status, asthma and atopy history,
BMI
Hoppin et al. 2007 Exposure: glyphosate ever use Chronic bronchitis
OR 0.99 (0.82–1.19)
Prospective cohort study of 20,908 participants in Logistic regression adjustments: age,
the Agricultural Health Study in Iowa and North state, sex, smoking (pack-years)
Carolina
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ADD/ADHD = attention deficit disorder/attention deficit hyperactivity disorder; BMI = body mass index; CFR = conditional fecundability ratio; CI = confidence
interval; HR = hazard ratio; OR = odds ratio
GLYPHOSATE 61
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Available data regarding respiratory effects in laboratory animals exposed to glyphosate are limited. In
mice, a 50% decrease in relative lung weight was observed following exposure to 250 mg/kg/day for 12
weeks (Ait Bali et al. 2017). No other observations were made in the lungs. Kumar et al. (2014) reported
an inflammatory respiratory response (evidenced by increased eosinophil and neutrophil counts, mast cell
degranulation, and production of IL-33, TSLP, IL-13, and IL-5) in anesthetized mice exposed intranasally
to glyphosate. Adam et al. (1997) designed a study to evaluate the effects of glyphosate technical (200
mg/kg), glyphosate + POEA (200 and 100 mg/kg, respectively), POEA alone (100 mg/kg), and
Roundup® in rats evaluated for 24 hours following intratracheal instillation (Adam et al. 1997). Control
rats received normal saline. Obvious clinical signs of adverse pulmonary effects and mortalities occurred
in each group except the saline controls. The study authors stated that the pulmonary effects were more
severe and lasted longer in rats treated with POEA alone or in combination with glyphosate compared to
responses in glyphosate only-treated rats. These results suggest POEA was more acutely toxic than
glyphosate to the lungs. No respiratory effects occurred in a 120-day study where rats were exposed to
250 mg/kg/day (Dar et al. 2019). No respiratory effects occurred in a 4-week study of rats intermittently
exposed to Roundup® at exposure levels as high as 360 mg/m3 (approximately 36 mg Roundup®/m3)
(EPA 1985c).
2.5 CARDIOVASCULAR
Two studies of Agricultural Health Study participants did not find associations between the use of
glyphosate-containing products and the risk of myocardial infarctions (Dayton et al. 2010; Mills et al.
2009); see Table 2-5 for details. An association was found between using a glyphosate-based herbicide
and vasculitic neuropathy in a 70 year old man who sprayed approximately 2,000 mL of the herbicide for
several hours without using protective gear 4 months before presenting with symptoms (Kawagashira et
al. 2017). In case series reports, abnormal electrocardiogram (EKG) readings have been found in patients
ingesting large doses of glyphosate-containing products (Kim et al. 2014; Lee et al. 2000, 2008; Moon
and Chun 2010; Moon et al. 2018; Talbot et al. 1991). The most commonly reported alterations included
prolonged QTc interval and sinus tachycardia. In the most severe poisoning cases, hypotension and shock
have been reported (Picetti et al. 2018; Roberts et al. 2010; Sawada et al. 1988; Tominack et al. 1991).
Additionally, adverse cardiovascular events (myocardial injury, shock, ventricular dysrhythmia, or
cardiac arrest) have been reported among patients who ingested glyphosate (Moon et al. 2018).
No data were available regarding evaluation of cardiovascular endpoints in laboratory animals exposed to
glyphosate technical or glyphosate formulations by any exposure route.
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2.6 GASTROINTESTINAL
Gastrointestinal symptoms are commonly reported in case series reports of patients who ingested
glyphosate products. In numerous reports, over 40% of the patients reported nausea/vomiting (Eriguchi et
al. 2019; Lee et al. 2000, 2008; Luo et al. 2019; Picetti et al. 2018; Roberts et al. 2010; Sawada et al.
1988; Tominack et al. 1991). Other effects reported included abdominal pain (Lee et al. 2000, 2008;
Moon and Chun 2010; Roberts et al. 2010; Sawada et al. 1988; Talbot et al. 1991), sore throat (Lee et al.
2000; Tominack et al. 1991), poor appetite (Luo et al. 2019), and damage to mucosal tissue in the mouth
and esophagus (Chang et al. 1999; Picetti et al. 2018; Sawada et al. 1988; Talbot et al. 1991; Tominack et
al. 1991). One case study reported gastric ulcer and a large pyloric antrum ulcer (Luo et al. 2019). In a
woman who accidentally ingested glyphosate-surfactant herbicide, a CT scan showed aspiration
pneumonitis and ileus of the intestine (Ozaki et al. 2017).
Several studies evaluated effects of glyphosate technical oral exposure in laboratory animals. The most
common effect was clinical signs of gastrointestinal disturbances. Such clinical signs are commonly
observed in studies of laboratory animals receiving bolus gavage doses of test substances, in which cases
the clinical signs may be at least partially the result of the method of gavage dosing. Diarrhea was
observed among rats gavaged once with glyphosate technical at 2,000 mg/kg (EPA 2013c).
Gastrointestinal disturbances (e.g., soft stool, diarrhea, few feces) were reported among pregnant rats
gavaged at 3,500 mg/kg/day during GDs 6–19 (EPA 1992e) and pregnant rabbits gavaged at
350 mg/kg/day during GDs 6–27 (EPA 1992f) or 175 mg/kg/day during GDs 8–20 (EPA 2017b). A slight
increase in observations of soft stool and/or diarrhea was noted in the rabbits dosed at 175 mg/kg/day
during GDs 6–27 as well (EPA 1992f). Soft stools were observed in rats exposed via the diet for
2 generations at concentrations resulting in estimated doses in the range of 2,219–2,633 and 3,035–
3,134 mg/kg/day for parental males and females, respectively (EPA 1992a). Mao et al. (2018) reported
that glyphosate added to the drinking water of rat dams from GD 6 through lactation and to F1 offspring
up to PND 125 at a concentration resulting in a daily dose of 1.75 mg/kg/day (the U.S. acceptable daily
intake [ADI]) resulted in modifications to the gut microbiota in early development, particularly among
prepubertal rats.
In a 2-year study of rats exposed via the diet (EPA 1991a, 1991b), inflammation of gastric squamous
mucosa was observed in females at an estimated dose level of 457 mg/kg/day; there were no signs of
gastrointestinal effects in males at estimated doses as high as 940 mg/kg/day. In another chronic-duration
oral rat study (EPA 1992d), there were no signs of treatment-related gastrointestinal effects at the highest
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Limited information was located regarding gastrointestinal effects in laboratory animals following oral
exposure to glyphosate formulations. Rats exposed daily for 6-12 weeks to 250 mg/kg/day exhibited a
decreased in total bacterial count in the gut (Aitbali et al. 2018). Lozano et al. (2018) reported significant
differences in microbiome genomic diversity, characterized by an increase in the Bacteroidetes family
S24-7 and a decrease in Lactobacillaceae, between treated female rats exposed to 5,000 ppm of Roundup
for 673 days when compared to control males, control females, and treated males. The study found that
Roundup had a direct selective bactericidal action on isolated gastrointestinal strains. In a study designed
to evaluate the effects of glyphosate technical (2,000 mg/kg), rats were administered glyphosate + POEA
(2,000 and 1,000 mg/kg, respectively), POEA alone (1,000 mg/kg), or Roundup® by gavage, followed by
24 hours of posttreatment observation (Adam et al. 1997). Control rats received normal saline. Two rats
in the POEA-only treatment group died. Diarrhea was noted in all groups except the control group. The
study authors stated that the groups given POEA or mixtures that included POEA experienced more rapid
and severe diarrhea than those given glyphosate alone. These results suggest that POEA was more acutely
toxic than glyphosate to the gastrointestinal system. Mao et al. (2018) reported that Roundup® added to
the drinking water of rat dams from GD 6 through lactation and to F1 offspring up to PND 125 at a
concentration designed to deliver a daily dose of 1.75 mg glyphosate/kg/day (the U.S. glyphosate ADI)
resulted in modifications to the gut microbiota in early development, particularly among prepubertal rats.
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2.7 HEMATOLOGICAL
2.8 MUSCULOSKELETAL
De Roos et al. (2005b) did not find an association between glyphosate use and the risk of rheumatoid
arthritis among participants of the Agricultural Health Study. In a subsequent study of female spouses of
licensed pesticide applicators, Parks et al. (2016) reported a weakly positive association between spousal
use of glyphosate and risk of rheumatoid arthritis (based on incident cases). See Table 2-5 for additional
study details.
No data were available regarding evaluation of musculoskeletal endpoints in laboratory animals exposed
to glyphosate technical or glyphosate formulations by any exposure route.
2.9 HEPATIC
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Human studies evaluating the relationship between glyphosate and hepatic endpoints is limited. One
retrospective cohort study reported acute liver failure as a complication associated with organ injury (Cho
et al. 2019). In a case-control study evaluating the association between glyphosate and patients with
nonalcoholic steatohepatitis (NASH), Mills et al. (2019) reported significantly higher levels of glyphosate
residue in NASH patients compared to non-NASH (p=0.008) patients. Furthermore, a dose-dependent
increase of glyphosate exposure was observed with advanced stages of fibrosis (stage 2, 3 or 4). No other
information was located regarding hepatic effects in humans exposed to glyphosate-containing products.
The potential for glyphosate technical to cause liver toxicity was evaluated in studies of rats and mice. In
a 7-day study of pregnant rats, the liver had a 19-23% increase in thiobarbituric acid reactive substances
(TBARS) levels in liver tissue compared to controls, following exposure to 500 mg/kg/day by oral gavage
(Almeida et al. 2017). In rats orally administered glyphosate for 28-days up to 10 mg/kg bw/day, no
treatment related findings were reported after gross necropsy. Further, no significant differences in liver
weights were reported between glyphosate treated groups and the control (Milic et al. 2018). However,
ROS levels in the liver were significantly increased at 10 mg/kg bw/day, while TBARS concentrations
decreased at 0.5, 1.75 and 10 mg/kg bw/day compared to controls. GHS levels in liver decreased by
22.7% and 27% at 1.75 and 10 mg/kg bw/day concentrations, respectively (Milic et al. 2018). Similarly,
GHS peroxidase (GSH-Px) activity in the liver was noticeably higher among rats exposed to 0.5, 1.75 and
10 mg/kg bw/day glyphosate compared to controls. Elevated levels of GSH-Px is reflective of glyphosate
inducing the antioxidant defense system in the liver (Milic et al. 2018).
In a 13-week rat dietary study of glyphosate technical, increases in liver weight and serum ALT were
observed in males at 1,678 mg/kg/day; increased liver weight and increased serum AP, ALT, and bile
acids were noted in females at 3,393 mg/kg/day. There were no indications of treatment-related liver
effects among male and female rats treated via the diet for 2 generations at estimated doses as high as
1,234–1,273 mg/kg/day (EPA 2013a) or other rats treated for 2 years to doses as high as 940–
1,183 mg/kg/day (EPA 1991a, 1991b). Male mice exposed via the diet for 13 weeks at doses ≥2,273
mg/kg/day exhibited increased mean relative liver weight (4–9% greater than controls) in the absence of
histopathologic liver lesions; there were no effects on liver weight in similarly-treated female mice at
doses up to and including 11,977 mg/kg/day (NTP 1992). Male mice exposed via the diet for 2 years at an
estimated dose of 4,945 mg/kg/day exhibited increased incidence of histopathologic central lobular
hepatocyte necrosis; there was no evidence of treatment-related liver effects in similarly-treated female
mice at an estimated dose of 6,069 mg/kg/day (EPA 2015a).
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Following oral exposure to glyphosate (1.0 g/L in drinking water) for 72 weeks, wild type and multiple
myeloma model mice (Vk*MYC strain) showed hepatic fibrosis and hematological abnormalities
including decreases in hemoglobin levels (i.e. anemia); lower levels of platelet counts and hematocrit
were observed in model multiple myeloma mice (Wang et al. 2019). This study was part of a larger effort
to understand the effect of glyphosate on multiple myeloma development, which is discussed in Section
2.19.
Rabbits administered repeated dermal applications of glyphosate technical at doses in the range of 100–
5,000 mg/kg/application for 21 days exhibited no evidence of treatment-related hepatic effects (EPA
1992c). However, male albino rats intraperitoneally exposed to 134.95 mg/kg/day glyphosate technical
for up to two weeks showed significantly increased serum AST, ALT, and ALP, decreased serum GSH,
increased hepatic nitric oxide, and increased hepatic lipid peroxidation, which the author attributed to
impairment of liver enzymes and hepatic metabolism (El-Shenawy 2009).
Two-week intraperitoneal exposure of albino rats to 269.9 mg/kg/day Roundup® demonstrated the same
liver effects as intraperitoneal exposure to 134.95 mg/kg/day glyphosate technical, including increased
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serum AST, ALT, and ALP, decreased serum GSH, increased hepatic nitric oxide, and increased hepatic
lipid peroxidation. Most of these observed effects were similar in both Roundup®-exposed and
glyphosate-exposed rats. However, compared to controls, rats exposed to glyphosate technical showed a
larger increase in hepatic nitric oxide than rats exposed to Roundup® (72% increase and 21% increase
respectively). Conversely, the increase in hepatic lipid peroxidation compared to controls was much more
pronounced in Roundup ®-exposed rats than in glyphosate-exposed rats (630% increase and 432%
increase respectively) (El-Shenawy 2009).
In vivo metabolome and proteome profiling of liver obtained from rats chronically exposed to long-term
exposure at low levels of Roundup® (4 ng/kg bw/day) for two years indicate effects to the liver including
metabolite alterations associated with non-alcoholic fatty liver disease and steatohepatosis (Mesnage et al.
2017). Metabolome profiling, or the analysis of metabolites characterizing the range of chemical
processes, analogous to chemical fingerprinting, revealed a lipotoxic condition, oxidative stress, and
markers of hepatotoxicity in the liver (Mesnage et al. 2017). Results from the proteome analysis, which
characterizes the expression of protein products and their interaction, reported rats exposed to Roundup ®
had alterations reflective of peroxisomal proliferation, steatosis, and necrosis (Mesnage et al. 2017).
2.10 RENAL
Available human data regarding the possible association between exposure to glyphosate and risk of renal
effects is limited to a few case-control studies, two case reports and one retrospective cohort study. One
case-control study of patients with chronic kidney disease found an increased risk of chronic kidney
disease among glyphosate applicators (Jayasumana et al. 2015). However, uncertainty regarding an
association between exposure to glyphosate-containing products and risk of chronic kidney disease
includes the finding that the applicators were also exposed to high levels of calcium, magnesium, barium,
strontium, iron, titanium, and vanadium by drinking water from abandoned wells. In the case of a 55 year
old man who ingested 200 mL of a glyphosate formulation, acute renal failure occurred (Picetti et al.
2018). Acute kidney injury and metabolic acidosis occurred in a woman who accidentally ingested
glyphosate-surfactant herbicide (Ozaki et al. 2017). Acute kidney injury associated with glyphosate-based
herbicide ingestion was also reported in a retrospective cohort study as a complication associated with
organ injury (Cho et al. 2019).
Several studies evaluated possible renal toxicity in laboratory animals treated with glyphosate technical.
In a 2-generation reproductive toxicity study (EPA 2013a), slightly increased absolute and relative kidney
weights (7–11% greater than controls) were reported among F0 parental female rats dosed at
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1,273 mg/kg/day; there was no evidence of histopathologic kidney lesions. Therefore, the slightly
increased kidney weight was not considered to represent an adverse effect. During 2 years of dietary
treatment of rats, urinalysis revealed increased specific gravity of urine and decreased urinary pH among
males treated at an estimated dose of 940 mg/kg/day (NOAEL=362 mg/kg/day); there were no signs of
treatment-related renal effects in urinalysis results from females treated at an estimated dose as high as
1,183 mg/kg/day (EPA 1991a, 1991b). Papillary necrosis (males and females) and decreased pH of urine
(males only) were observed in a study of rats administered glyphosate in the diet for up to 2 years at
estimated doses of 1,214 mg/kg/day (males) and 1,498 mg/kg/day (females); respective NOAELs were
361 and 437 mg/kg/day (EPA 2015c). Another 2-year rat study reported decreased pH of urine among
males treated at 1,000 mg/kg/day (NOAEL=300 mg/kg/day); no renal effects were observed in females at
doses as high as 1,000 mg/kg/day (EPA 2015c). Female mice treated for 2 years at an estimated dose of
6,069 mg/kg/day exhibited significantly increased incidence of renal proximal tubule epithelial basophilia
and hypertrophy (NOAEL=968 mg/kg/day); there was no evidence of renal effects in similarly-treated
male mice at doses as high as 4,945 mg/kg/day (EPA 2015a).
Shorter-term studies on rodents exposed to glyphosate technical found signs of potential renal damage.
Myeloma model mice orally exposed to glyphosate (1.0 g/L in drinking water) for 72 weeks showed renal
damage, including tubular obstruction by casts (Wang et al. 2019). This study was part of a larger effort
to understand the effect of glyphosate on myeloma development, which is discussed in Section 2.19. In a
two-week study albino rats exposed intraperitoneally to 134.95 mg/kg/day glyphosate showed serum
changes indicative of potential kidney effects. Compared to control rats, glyphosate-exposed rats had
33.8% decreased serum creatinine, 110% increased serum urea, and 146% increased uric acid. Similar
results were seen in the male rats exposed to 269.9 mg/kg/day Roundup® (El-Shenawy 2009).
2. HEALTH EFFECTS
Roundup® Weedkiller at dose levels ranging from 250 to 2,500 mg/kg (Wunnapuk et al. 2014). There is
some uncertainty regarding the role of glyphosate in the reported effects.
2.11 DERMAL
One woman developed skin lesions after accidental dermal exposure to glyphosate in an herbicide and
was diagnosed with toxic hand dermatitis (Elsner et al. 2018). After treatment did not fully resolve the
lesions, she was diagnosed with koebnerization of psoriasis caused by acute irritant contact dermatitis.
In another study, Camacho and Mejia (2017) evaluated the association between aerial applications of
glyphosate in Colombia and health effects of individuals living in the sprayed areas. The association was
assessed using individual medical record data and information about Colombia’s aerial spraying program.
Several health outcomes including dermatological effects. Their results observed that for each additional
square kilometer increase in area sprayed with glyphosate there was an increase in the proportion of
dermatological diagnoses 7 to 15 days following exposure.
One study evaluated the potential dermal toxicity of glyphosate in humans. In an experimental study (see
Table 2-5), a single application of Roundup® to intact skin for 24 hours did not result in irritation
(Maibach 1986). When applied to abraded skin, erythema was noted in 42% of the subjects after
24 hours. Mild skin irritation was observed in a repeated exposure test study (Maibach 1986). No skin
irritation was observed in a Draize skin sensitization test or in a photosensitivity/photoirritation test
(Maibach 1986).
Available information regarding dermal effects in animals is limited. Minor dermal irritation was
reported in response to dermally-applied glyphosate technical. At the application site, very slight
erythema and edema were observed in rabbits during 21 days of repeated dermal application of
glyphosate technical at 5,000 mg/kg/application; no dermal effects were seen at doses ≤1,000 mg/kg/
application (EPA 1992c). According to EPA (1993), glyphosate is considered a slight dermal irritant
following acute dermal application.
2.12 OCULAR
In a study of wives of commercial pesticide applicators, no association was found between glyphosate use
among the wives and retinal degeneration (Kirrane et al. 2005); see Table 2-5 for details. In a case series
report of 1,513 ocular exposures to glyphosate, minor symptoms (primarily transient irritation) were
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observed in 70% of the cases; most (99%) complained of eye pain (Acquavella et al. 1999). Moderate
effects, such as persistent irritation or low-grade corneal burns or abrasions, were observed in about 2% of
the cases. Among the cases with moderate effects, 93% reported eye pain, 20% reported lacrimation, and
27% reported blurred vision.
Two chronic-duration oral studies included ophthalmoscopic examinations of laboratory animals exposed
to glyphosate technical. EPA (1991a, 1991b) reported significantly increased incidence of lens
abnormalities in male rats treated via the diet for 2 years at an estimated dose of 940 mg/kg/day; there
were no indications of a treatment-related ocular effect in female rats at the highest estimated dose level
(1,183 mg/kg/day). No signs of treatment-related ocular effects were seen among dogs treated via
capsule for 1 year at estimated doses as high as 500 mg/kg/day (EPA 1986a).
According to EPA (1993), glyphosate is considered mildly irritating to the eye following ocular
instillation. According to FAO and WHO (2016), glyphosate was moderate to severely irritating to the
rabbit eye. EFSA (2015) stated that glyphosate acid was a severe ocular irritant, but that salts of
glyphosate do not require classification as ocular irritants. There were no signs of exposure-related
effects in ophthalmologic examinations of rats intermittently exposed to Roundup® for 4 weeks at
exposure levels as high as 360 mg/m3 (approximately 36 mg Roundup®/m3) (EPA 1985c).
2.13 ENDOCRINE
In a weight-of-evidence approach to evaluate the potential for glyphosate to affect the endocrine system,
EPA (2015b) subjected glyphosate to the Endocrine Disruptor Screening Program Tier 1 (a battery of in
vitro assays designed assist in evaluation of the potential for a substance to interact with estrogen,
androgen, or thyroid signaling pathways). EPA evaluated results from the battery of in vitro assays and
relevant laboratory mammalian and wildlife studies. Using this approach, EPA determined that there is
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no convincing evidence of potential interaction between glyphosate and estrogen, androgen, or thyroid
pathways in mammals or wildlife. Included in the evaluation of the estrogen pathway were estrogen
receptor (ER) binding assays, an ER transactivation assay, aromatase and steroidogenesis assays, a fish
short-term reproduction assay, and mammalian and wildlife studies that assessed female reproductive
parameters. Included in the evaluation of the androgen pathway were androgen receptor (AR) binding
and steroidogenesis assays, a fish short-term reproduction assay, Hershberger and male pubertal assays,
an AR transactivation assay, and mammalian and wildlife studies that assessed male reproductive
parameters. Included in the evaluation of the thyroid pathway were male and female pubertal assays, an
amphibian metamorphosis assay, and mammalian and wildlife studies that assessed thyroid parameters
Refer to EPA (2015b) for study summaries and EPA (2015d) for DERs from most studies that contributed
to EPA’s conclusions regarding the potential for glyphosate to affect the endocrine system.
Limited information was located regarding the potential for glyphosate formulations to affect the
endocrine system. While one study reported degeneration of pancreatic acinar cells and islets of
Langerhans after male Wistar rats were exposed to 14.4, 375, or 750 mg/kg/day of the herbicide Bushfire
via drinking water (Tizhe et al. 2018), most of the observed endocrine effects in glyphosate formulation
animal studies involved changes in hormone levels. Romano et al. (2010) reported dose-related 30–50%
decreased serum testosterone in young male rats gavaged with Roundup Transorb® at 5–250 mg/kg/day
during postpartum days 23–53. Romano et al. (2012) implicated disruption of gonadotropin expression as
a mechanism of action for glyphosate-induced effects on male rat sexual development. Pregnant C57B1/6
mice exposed to 420 mg/kg/day Roundup® in their drinking water showed no difference in pancreas
weight compared to controls, but their male F1 offspring had 195% higher intratesticular testosterone, an
estimated 60% increase in plasma LH, and a 11% increase in β-LH pituitary protein compared with male
F1 controls (Teleken et al. 2019).
2. HEALTH EFFECTS
approximately 14% decrease in luteinizing hormone, and approximately 31% increase in prolactin) at
doses as low as 3.6 mg/kg/day (Owagboriaye et al. 2017).
However, in an exposure study that exposed male Sprague-Dawley rats to either glyphosate technical (2.5
mg/kg/day or 25 mg/kg/day) or the glyphosate formulation Glyfonova (25 mg/kg/day) via their drinking
water, no changes in intratesticular testosterone levels were observed. While the rats exposed to
Glyfonova showed a statistically significant upregulation in P450 encoding genes in the testes, the authors
concluded this was not indicative of endocrine effects (Johansson et al. 2018). Nevertheless, other studies
reported changes in gene and protein expression attributed to glyphosate formulation exposures (Romano
et al. 2012; Teleken et al. 2019; Varayoud et al. 2017).
2.14 IMMUNOLOGICAL
Studies examining possible associations between glyphosate exposure and asthma risk or rheumatoid
arthritis risk are discussed in Sections 2.4 and 2.8, respectively.
Limited information is available regarding immunological effects. There was no evidence of treatment-
related effects on spleen or thymus of mice administered glyphosate technical in the diet for 28 days at
estimated doses as high as 1,447.5 mg/kg/day and no evidence of treatment-related effects on splenic anti-
sheep red blood cell (SRBC) anti-body forming cell (AFC) responses to SRBC (EPA 2013b). EPA
(1992d) reported significantly increased incidences of lymphocytic hyperplasia in the thymus from female
rats administered glyphosate technical in the diet for up to 26 months at doses of 3.37, 11.22, and
34.02 mg/kg/day (13/32, 18/37, and 17/34, respectively, versus 5/25 controls). However, EPA (1992d)
did not consider the lesion to be compound-related because the lesion occurs spontaneously in older rats
and is quite variable in the thymus, there was no apparent effect on lymphocytes in the spleen (a much
less variable indicator for lymphocytic hyperplasia), and the severity of the lesion was similar among
controls and glyphosate-treated groups. Kumar et al. (2014) reported an inflammatory respiratory
response (evidenced by increased eosinophil and neutrophil counts, mast cell degranulation, and
production of interleukin-33, thymic stromal lymphopoietin, interleukin-13, and interleukin-5) in
anesthetized mice exposed intranasally to glyphosate.
2.15 NEUROLOGICAL
2. HEALTH EFFECTS
association between glyphosate exposure and Parkinson’s disease (see Table 2-5 for details) (Kamel et al.
2007). In a cross-sectional study conducted on farmers in China, Zhang et al. (2018) reported glyphosate
use was not associated with increased odds or incidence rates of abnormalities of peripheral nerve
conduction.
One case study found that a man who ingested 200 ml of glyphosate developed Parkinson’s symptoms 4
years after exposure (Eriguchi et al. 2019). A spatial analysis of exposure to pesticides in Washington
State found an association between glyphosate exposure and increased odds of premature mortality
attributable to Parkinson’s disease (OR = 1.33; 95% CI = 1.06-1.67) (Caballero et al. 2018).
Several animal studies in rats and mice have evaluated the neurological effects of glyphosate. Mice
exposed once to 250 mg/kg/day RoundUp® via gavage showed a decrease in aversive memory
performance (Ait Bali et al. 2019). However, no neurological effects were seen in mice given ≤500
mg/kg/day once by oral gavage (Ait Bali et al. 2017; Aitbali et al. 2018). At 6-12 weeks of daily
exposure, mice showed behavioral changes in locomotor activity, increase of anxiety and depression-like
behavior levels, decreased memory performance and decreased grooming time with 250 mg/kg/day
RoundUp® exposure (Ait Bali et al. 2017; Ait Bali et al. 2019; Aitbali et al. 2018). The observed
neurobehavioral changes were attributed to neurodevelopmental impairment as evidenced by a reduction
in serotonin (5-HT) immunoreactivity following 6 or 12 weeks of oral exposure to 250 or 500 mg/kg/day
RoundUp® and a reduction in tyrosine hydroxylase (TH) immunoreactivity following 12 weeks of
exposure to 250 or 500 mg/kg/day RoundUp® (Ait Bali et al. 2017).
Ait Bali et al. (2019), measured acetylcholinesterase activity in rat whole brain, prefrontal cortex and
hippocampus, which was inhibited at ≥250 mg/kg/day by >25%, >35%, >25%, respectively. Inhibition in
all measured parts was dose-dependent (Ait Bali et al. 2019). In pregnant rats, glutathione was decreased
by 16-26% following exposure to 500 mg/kg/day RoundUp® on days 1 to 7 of pregnancy (Almeida et al.
2017). In male offspring exposed in utero, during lactation then from post-natal day 21 to 60 to 70
mg/kg/day RoundUp®, there was a 23% inhibition of hippocampus cholinesterase after post-natal day 60
(Cattani et al. 2017). Oxidative damage, astrocyte dysfunction, glutamate excitotoxicity, and
misregulation of cholinergic transmission were also seen (Cattani et al. 2017).
In rats treated via the diet for 13 weeks at doses as high as 1,547–1,631 mg/kg/day and in rats
administered glyphosate technical once by gavage at up to 2,000 mg/kg, there was no evidence of
treatment-related neurotoxicity seen by functional observational battery, motor activity testing, and gross
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and histopathologic examination of brain and peripheral nervous tissue (EPA 2013c). However, clinical
signs included decreased activity, subdued behavior, and hunched posture.
Glyphosate technical was observed to affect monoaminergic neurotransmitters in the central nervous
system. In rats administered glyphosate orally up to 800 mg/kg bw/day for 6 days, serotonin
neurotransmitter levels were significantly decreased in a dose dependent manner at 75, 150 and 800
mg/kg bw in various regions of the brain including the striatum, hippocampus, prefrontal cortex,
hypothalamus and midbrain region (Martinez et al. 2018). Similarly, dopamine and norepinephrine levels
were reported to decrease with increasing concentrations of glyphosate starting at 75 mg/kg bw/day.
Turnover rates of the neurotransmitters were measured, and their metabolites were altered; there was a
significant increase in turnover between serotonin and dopamine, and a decrease in turnover with
norepinephrine (Martinez et al. 2018).
Rats orally exposed to 5 mg/kg/day of glyphosate or glyphosate-based formulation perinatally from day 9
gestation to day 22 post-natal were found to have increased expression of synaptophysin a marker of
synaptic terminals in the hippocampus of both groups (Dechartres et al. 2017). Maternal behavior was
also observed; at day 1 post-natal, dams were observed to spend less time licking and grooming offspring
whereas between day 2 and 6 post-natal, more time was spent with offspring.
In vitro studies have also examined glyphosate and glyphosate-based herbicides for neurotoxicity.
Glyphosate and an herbicide containing glyphosate isopropylamine as its active ingredient were tested in
vitro at concentrations of 0.005% to 0.0005%. Although no effect was observed for pure glyphosate,
glyphosate-based herbicides were reported to interfere with myelination and also as a demyelinating agent
in a dose-dependent manner (Szepanowski et al. 2018). However, after testing for demyelination using
glyphosate and isopropylamine additively (rather than as formulated), the authors note that this effect may
be due to undisclosed additives. Neither glyphosate (pure) nor glyphosate-based herbicide were found to
impair neurite development (Szepanowski et al. 2018).
2.16 REPRODUCTIVE
No association between glyphosate use and fecundability was found among women living at farms in
which pesticides were used and were involved in pesticide activities (Curtis et al. 1999). This study also
reported an association with improved fecundability when the women were not involved in pesticide
activities; see Table 2-5 for additional information. Sanin et al. (2009) examined the fertility of women
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living in regions of Columbia with varying agricultural usage of glyphosate. Although time to pregnancy
varied widely by region, no significant associations were found with level of glyphosate usage.
In another study, Camacho and Mejia (2017) evaluated the association between aerial applications of
glyphosate in Colombia and miscarriages by women living in the sprayed areas. Their results observed a
positive association. For each additional square kilometer increase in area sprayed with glyphosate there
was an increase in the number of miscarriage diagnoses. However, the authors note the way miscarriage
was defined in the study may overestimate the number of actual miscarriages. In the study, miscarriage
was defined when a mother was observed to have attended a prenatal care visit, but a corresponding birth
registry was not located after 10 months.
Rodent studies frequently reported reproductive effects in males. Increased incidence of prostatitis was
reported among male rats receiving glyphosate technical from the diet for up to 2 years at estimated doses
of ≥361 or 1,214 mg/kg/day (EPA 2015c). In male rats exposed to 375 mg/kg/day of glyphosate for 8
weeks, a significant decrease in abnormal sperm rate, increased testes malondialdehyde levels, decreased
glutathione levels, DNA damage in sperm cells, decreased sperm concentration, and degeneration of
Sertoli cells in testes were observed (Avdatek et al. 2018). Cassault-Meyer et al. (2014) reported
increased abnormal sperm morphology in rats receiving Roundup® Grand Travaux Plus from the
drinking water for 8 days at 640 mg/kg/day (the only dose level tested). Male F1 offspring of C57B1/6
mice exposed to 420 mg/kg/day Roundup® in utero through the end of lactation showed an estimated 5%
decrease in epithelial height and a 70% reduction of sperm in the cauda epididymis (Teleken et al. 2019).
Male Kumming mice exposed to 60, 180, or 540 mg/kg/day Roundup® showed no reproductive effects at
the lowest dose, but had significantly decreased sperm motility and increased sperm abnormality at the
higher two doses (Jiang et al. 2018). Two low dose studies using glyphosate and glyphosate-based
herbicides with exposures ranging from 1.75 mg/kg/day to 25 mg/kg/day showed no effects on sperm
parameters or evidence of lesions or degeneration (Johansson et al. 2018; Manservisi et al. 2019).
However, male albino rats orally exposed to Roundup® for 12 weeks showed testicular degeneration and
increased sperm abnormalities in doses as low as 3.6 mg/kg/day (Owagboriaye et al. 2017).
While most studies on male rodents showed reproductive effects, reproductive effects in female rodents
exposed to glyphosate or glyphosate formations were not observed consistently. In female rats exposed to
126 mg/kg/day of a glyphosate-based herbicide for 60 days, relative ovary weight decreased by 38%
compared to controls (Hamdaoui 2018). Additionally, there was a 109% increase in atretic follicles, 14%
increase in malondialdehyde levels in ovary homogenates, decreased enzymatic antioxidant activity in
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ovaries, necrosis, and vacuolization of follicles and oocytes in ovaries (Hamdaoui 2018). In pregnant rats
acutely exposed, ovaries were lighter, implanted sites decreased by 42%, total number of corpus luteum
were reduced, and pre-implantation loss increased following exposure to 500 mg/kg/day (Almeida et al.
2017). However, no reproductive effects were reported in pregnant female C57B1/6 mice orally exposed
to 420 mg/kg/day (Teleken et al. 2019) or in female Wistar rats subcutaneously exposed to 0.5, 5, or 50
mg/kg/day of a glyphosate formulation (Varayoud et al. 2016).
Anifandis et al. (2017) investigated the effects of direct exposure of human sperm samples to 1 mg/L
Roundup® (corresponding to 0.36 mg/L of glyphosate) on mitochondrial integrity and motility. Results
found that the percentage of sperm motility in Roundup-treated samples upon one hour of incubation was
significantly lower than in controls; after three hours of incubation, the percentage of sperm motility in
Roundup-treated samples was also significantly lower than in controls. Mitochondrial incorporation of
CMX dye was reduced in sperm samples exposed to Roundup at the first hour of incubation, indicating
mitochondrial dysfunction. Anifandis et al. (2018) also found that human sperm motility decreased more
significantly in samples exposed to 0.36 mg/L of glyphosate than in control samples at the first hour of
incubation. This study also found that sperm DNA fragmentation of glyphosate-treated samples was not
significantly different than sperm DNA fragmentation in controls.
Zhang et al. 2019b evaluated in vitro the effect of glyphosate on the maturation of oocytes. Mouse
oocytes were exposed up to 500 µM glyphosate for either 2 or 14 hours. Glyphosate was reported to
reduce the rates of germinal vesicle breakdown (GVBD) and first polar body extrusion (PBE), which are
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key events in oocyte maturation. Glyphosate was also observed to increase ROS levels, damage DNA,
induce abnormal spindle morphology, and impair mitochondrial aggregation. Consequently, findings
suggest glyphosate disrupts the development and maturation of oocytes by generating oxidative stress and
inducing early apoptosis (Zhang et al. 2019b).
Vanlaeys et al. (2018) investigated the effects of various concentrations of glyphosate and glyphosate-
based herbicide formulations on the immature mouse Sertoli cell line (TM4). During the first 24 hours of
treatment, glyphosate at concentrations ranging from 10 ppm to an agricultural dilution 1000 times
greater did not impact cell viability, while glyphosate-based formulations resulted in dose-dependent cell
death. Glyphosate–based formulations also inhibited glutathione-S-transferase activity, but glyphosate
alone did not. Additionally, glyphosate-based formulations induced accumulation of intracellular lipids.
Both glyphosate and glyphosate-based formulations resulted in mitochondrial dysfunction signified by
reduced Succinate dehydrogenase activity. The authors concluded that herbicide-induced mitochondrial
function alterations are formulation-dependent. The study also assessed TM4 cell viability after acute or
24-hour exposure to Glyphogan formulants or Glyphogan, and results indicate that this mixture of
compounds leads to rapid induction of cell mortality. Glyphogan formulants at sub-agricultural doses
were able to rapidly penetrate and accumulate in cells.
2.17 DEVELOPMENTAL
Several epidemiology studies have examined possible associations between glyphosate use and
developmental toxicity; these studies are summarized in Table 2-5. Given that only one study examined
each endpoint and the lack of quantification of glyphosate exposure across studies, these results were not
considered sufficient for drawing conclusions on the risk of developmental toxicity associated with
glyphosate exposure in humans. Arbuckle et al. (2001) reported a positive association between maternal
preconception exposure to glyphosate and increased risk of spontaneous abortion (miscarriage). Garry et
al. (2002) reported a positive association between phosphonamino- herbicides (glyphosate, Roundup®)
exposure and parent-reported attention deficit disorder/attention deficit hyperactivity disorder
(ADD/ADHD). No associations were found between paternal exposure and risk of miscarriages (Savitz et
al. 1997), preterm delivery (Savitz et al. 1997), small for gestational age risk (Savitz et al. 1997), or
congenital malformations (Garcia et al. 1998). Similarly, no associations were found between maternal
glyphosate exposure and birth weight (Sathyanarayana et al. 2010; Parvez et al. 2018), neural tube defects
(Rull et al. 2006), or head circumference (Parvez et al. 2018).
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Developmental endpoints were evaluated in animals orally exposed to glyphosate technical. Depressed
weight and increased incidence of unossified sternebrae were observed in fetuses from rat dams treated by
gavage at 3,500 mg/kg/day during GDs 6–19 (EPA 1992e). This dose level resulted in maternal toxicity,
thus the developmental effects noted may be secondary to the maternal effects. Increased incidence of
kidney tubular dilation was reported for F3b male weanlings in a 3-generation study of glyphosate
technical (98.7% purity) administered to male and female Sprague-Dawley rats in the diet at an estimated
dose level of 30 mg/kg/day; the reported NOAEL was 10 mg/kg/day (EPA 1992g). However, there were
no signs of treatment-related effects on kidneys of rat offspring in two subsequent 2-generation rat studies
at dose levels up to 1,234 mg/kg/day (EPA 2013a) or 3,134 mg/kg/day (EPA 1992a). Therefore, the
finding of increased incidence of kidney tubular dilation in the 3-generation rat study (EPA 1992g) was
considered a spurious result rather than a glyphosate-induced adverse developmental effect. In one 2-
generation oral rat study, exposure via the diet at an estimated dose level of 1,234 mg/kg/day resulted in
delayed preputial separation in male pups (EPA 2013a). In the other 2-generation study, the highest dose
level (3,134 mg/kg/day) resulted in up to 14–20% depressed pup body weight and/or body weight gain
during the lactation period (EPA 1992a), though the authors state it is unclear if this effect is compound
related or due to the ingestion of the treated diet. There were no apparent treatment-related developmental
effects in a study of rabbits treated by gavage at up to 350 mg/kg/day glyphosate technical during GDs 6–
27 (EPA 1992f). No developmental effects were seen in rat pups exposed to 2 mg/kg/day every 48 hours
on post-natal day 1 to 7 (Guerrero Schimpf et al. 2017). Depressed mean fetal weight (8% less than
controls) was noted in a study of pregnant rabbits administered glyphosate acid at 300 mg/kg/day during
GDs 8–20 (EPA 2017b). However, on a per litter basis, there was no statistically significant difference
between controls and glyphosate-treated groups. Therefore, the 300 mg/kg/day dose level is considered a
NOAEL for fetal body weight. In a 3-generation study, female Sprague-Dawley rats were acutely exposed
to 25 mg/kg/day of glyphosate technical during GDs 8-14 (Kubsad et al. 2019). Offspring in the F1
generation showed delays in puberty in males and decreases in weaning weights of both sexes. More
serious effects were observed in the F2 and/or F3 generations: significant increases in testis disease,
prostate disease, kidney disease, ovary disease, obesity, tumors and parturition abnormalities. Almost a
third of F2 generation females (7/20) died during late gestation or experienced litter mortality, whereas
neither of these abnormalities were observed in the 16 controls.
Pham et al. (2019) administered glyphosate or Roundup® 3 Plus at doses of 0.5, 5 or 50 mg/kg/day to
pregnant rats from embryonic day 10.5 to 20 days postpartum. Male offspring were assessed for
reproductive effects after sacrifice at 5 days, 20 days, 35 days, or 8 months old. Significant decreases in
sperm counts were observed in males prenatally exposed to both formulations of glyphosate: 0.5
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mg/kg/day of Roundup® and 5 mg/kg/day of glyphosate were associated with 89% and 84% reductions,
respectively. Exposure to glyphosate technical was associated with decreased serum testosterone and
altered testes morphology in rats sacrificed at 20 days old. Testosterone was also reduced in 8-month old
rats exposed to Roundup®.
Developmental endpoints were evaluated in three open-literature studies that employed oral exposure to
glyphosate formulations. The specific role of glyphosate in the reported results is uncertain. Dallegrave
et al. (2003) observed an increased incidence of skeletal malformations in fetuses from rat dams gavaged
with Roundup® at 500 mg/kg/day during GDs 6–15. Dallegrave et al. (2007) reported decreased sperm
production and histopathologic testicular lesions in offspring of rat dams gavaged with Roundup® at
50 mg/kg/day during gestation and lactation. Romano et al. (2010) reported decreased epithelial
thickness and increased luminal diameter in seminiferous tubules of male rat pups treated with Roundup
Transorb® by gavage at 5 mg/kg/day on postpartum days 23–53 and delayed preputial separation at a
dose level of 50 mg/kg/day. An additional study on C57B1/6 mice also documented developmental
effects on the reproductive system when male F1 offspring exposed to 420 mg/kg/day Roundup® in utero
through the end of lactation showed increased age at testes descent (Teleken et al. 2019).
Multi-generational rat studies using intermediate oral exposure to glyphosate-based herbicides found
developmental effects of varying severity. When pregnant F0 Sprague-Dawley dams were exposed to
1.75 mg/kg/day Roundup® Bioflow in their drinking water from gestation day 6 to postnatal day 120,
male and female offspring showed increased anogenital distance at postnatal day 4. Increased anogenital
distance was also observed in offspring of F0 dams exposed to glyphosate technical, but, unlike
Roundup® Bioflow exposure, glyphosate exposure was only associated with this effect in male offspring
(Manservisi et al. 2019). When pregnant F0 Wistar dams fed paste with 3.69 or 352.2 mg/kg/day of the
glyphosate-based herbicide MAGNUM SUPER II from gestation day 9 to lactation day 21,
developmental effects were observed in F2 offspring. F1 females from the lower exposure group gave
birth to offspring with a 2% decrease in fetal length, 6% decrease in body weight, and an increased risk of
being small for gestational age (RR= 2.43, 91% CI: 1.66, 3.55) compared to controls. F1 females from the
higher exposure group gave birth to offspring that showed increased fetal anomalies (conjoined fetuses
and abnormal limbs) compared to controls, as well as the fetal growth effects found in the lower exposure
group (Milesi et al. 2018).
In a study on rats exposed from gestation day 0 to post-natal day 21, exposure to a glyphosate formulation
was associated with impaired neurological development. Impaired recognition memory, whole brain
oxidative stress, decreased lipid peroxidation, and enzyme activity alterations were seen in female
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offspring rats exposed to 100 mg/kg/day Glifloglex® (Gallegos et al. 2018). In male offspring, impaired
memory was only seen at higher doses of 200 mg/kg/day. At 100 mg/kg/day, striatum
acetylcholinesterase activity was inhibited by 23%, in addition to other effects seen in females at the same
dose (Gallegos et al. 2018).
Chronic glyphosate exposure to pregnant mice at 0.5% glyphosate solution altered several biochemical
indices related to liver status and metabolism in the offspring. Serum triglyceride levels increased in
gestational day 19 fetuses and postnatal day 21 female offspring and total cholesterol was elevated in
postnatal day 7 (males) and 21 (female) offspring. LDL levels were noticeably elevated in postnatal day 7
mice and in females, AST levels were significantly increased suggesting damage to the liver. Histological
examination revealed clustering of monocytes, indicative of inflammation, in postnatal day 7 females and
hepatic lipid droplets in hepatocytes of the offspring mice, with effects more pronounced in males (Ren et
al. 2019). Overall, offspring mice exhibited hepatic steatosis and excessive lipid droplets formation within
hepatocytes suggesting glyphosate alters lipid metabolism (Ren et al. 2019).
Other developmental endpoints evaluated include developmental neurotoxicity. Frank et al. (2017)
conducted in vitro assays at concentrations ranging between 0.03 to 30 µM of glyphosate to examine
whether it disrupts normal cortical development. Glyphosate was not found to exert neurodevelopmental
toxicity in vitro.
No associations were found between glyphosate exposure and increased risks of diabetes (Montgomery et
al. 2008) or gestational diabetes (Saldana et al. 2007) in epidemiology studies (see Table 2-5). Metabolic
acidosis (Kim et al. 2014; Lee et al. 2008; Moon and Chun 2010; Tominack et al. 1991), hyperkalemia
(Kim et al. 2014; Lee et al. 2008; Moon and Chun 2010), and acute pancreatitis (Hsiao et al. 2008; Kim et
al. 2014; Moon and Chun 2010) have been reported in case series of individuals ingesting glyphosate;
metabolic acidosis was typically reported in >35% of the cases.
Hypothermia was reported among rats following single gavage dosing of glyphosate technical at
2,000 mg/kg (EPA 2013c).
2.19 CANCER
2. HEALTH EFFECTS
Lymphohematopoietic Cancers. From 2014 to 2016, several meta-analyses were conducted for
lymphohematopoietic cancers. The results of these analyses are presented in Table 2-6. The primary
literature used in these meta-analyses is discussed later in this section.
Schinasi and Leon (2014) conducted a systematic review and meta-analysis of 21 pesticide active
ingredients and chemical groups including glyphosate. The authors reported a positive association
between glyphosate use and B-cell lymphoma based on two studies (meta-relative risk [RR] 2.0; 95%
confidence interval [CI] 1.1–3.6) and a positive association between glyphosate use and non-Hodgkin’s
lymphoma (NHL) based on six studies (meta RR 1.5; 95% CI 1.1–2.0).
Chang and Delzell (2016) performed meta-analyses for NHL subtypes (diffuse large B-cell lymphoma,
B-cell lymphoma, chronic lymphocytic leukemia/small lymphocytic leukemia [CLL/SLL], and hairy-cell
leukemia), as well as other types of lymphohematopoietic cancers (leukemia, multiple myeloma, and
Hodgkin’s lymphoma). The authors reported a positive association between glyphosate use and the risk
of NHL (meta RR 1.3; 95% CI 1.0–1.6; six studies), multiple myeloma (meta RR 1.4; 95% CI 1.0–1.9;
four studies), and the NHL subtype B-cell lymphoma (meta RR 2.0; 95% CI 1.1–3.6; two studies). The
authors concluded that associations were statistically null for Hodgkin’s lymphoma (meta RR 1.1; 95%
CI 0.7–1.6; two studies), leukemia (meta RR 1.0; 95% CI 0.6–1.5; three studies); and the NHL subtypes
diffuse large B-cell lymphoma (meta RR 1.1; 95% CI 0.5–2.3; two studies), CLL/SLL (meta RR 1.3; 95%
CI 0.2–10; two studies), follicular lymphoma (meta RR 1.7; 95% CI 0.7–3.9; two studies), and hairy cell
leukemia (meta RR 2.5; 95% CI 0.9–7.3; two studies). Some of the RR CIs were wide, indicating
uncertainty in the point estimate.
The IARC Working Group conducted a meta-analysis for NHL using the same six studies as Schinasi and
Leon (2014) and Chang and Delzell (2016). The Working Group reanalyzed the data, but used the most
fully adjusted risk estimates for the studies by Hardell et al. (2002) and Eriksson et al. (2008) and
estimated a slightly lower meta-analysis relative risk (meta RR 1.3; 95% CI 1.03–1.65) (IARC 2017).
Zhang et al. (2019a) conducted a meta-analysis of the association between glyphosate exposure and NHL
based on five case-control studies and the 2018 update of the Agricultural Health Study. The most highly
exposed individuals had a 41% higher risk of NHL as compared to unexposed controls (meta RR 1.41;
95% CI 1.13–1.75).
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Table 2-6. Summary of Meta-Analyses of Results from Studies Examining Possible Association Between Self-
Reported Use of Glyphosate and Lymphohematopoietic Cancers
Meta-analysisa
Studies included in Number reporting relative risk or hazard ratio
Outcome analysis Number of participants glyphosate use (95% CI) Reference
Non- De Roos et al. 2003 650 cases/1,933 controls 36 cases/61 controls 1.5 (1.1–2.0) Schinasi and
Hodgkin’s De Roos 2005a 54,315 71 cases I2=32.7% Leon 2014
lymphoma Eriksson et al. 2008 1,163 cases/1,016 controls 29 cases/18 controls
Hardell et al. 2002 515 cases/1,141 controls 8 cases/8 controls
McDuffie et al. 2001 517 cases/1,506 controls 51 cases/133 controls
Orsi et al. 2009 244 cases/436 controls 12 cases/24 controls
Non- De Roos et al. 2003 Not stated Not stated 1.3 (1.03–1.65) IARC 2017
Hodgkin’s De Roos 2005a 54,315 Not stated I2=0.0%, p=0.589 for
lymphoma Eriksson et al. 2008 910 cases/1,016 controls 29 cases heterogeneity
Hardell et al. 2002 404 cases/741 controls 8 cases
McDuffie et al. 2001 517 cases/1,506 controls 51 cases
Orsi et al. 2009 244 cases/436 controls 12 cases
Non- De Roos et al. 2003 650 cases/1,933 controls 36 cases/61 controls 1.3 (1.0–1.6) Chang and
Hodgkin’s De Roos 2005a 49,211 71 cases I2=0.0%, p=0.84 for heterogeneity Delzell 2016
lymphoma Eriksson et al. 2008 995 cases/1,016 controls 29 cases/18 controls
Hardell et al. 2002 515 cases/1,141 controls 8 cases/8 controls
McDuffie et al. 2001 517 cases/1,506 controls 51 cases/133 controls
Orsi et al. 2009 244 cases/436 controls 12 cases/24 controls
Non- Leveque-Morlais et al. 127,282 Estimated 36% mHR 0.95 (0.77–1.18) Leon et al.
Hodgkin’s 2015 I2=57.0%, p=0.10 for 2019
lymphoma Kristensen et al. 1996 137,821 Estimated 38% heterogeneity
Alavanja et al. 1996 51,167 Estimated 83%
Non- McDuffie et al. 2001 517 cases/1,506 controls mOR 1.43 (1.11–1.83) Pahwa et al.
Hodgkin’s Cantor et al. 1992 622 cases/1,245 controls I2= not reported 2019
lymphoma Hoar et al. 1986 200 cases/1,005 controls
Zahm et al. 1990 201 cases/725 controls
Non- Andreotti et al.2018 54,251 Estimated 83% 1.41 (1.13–1.75) Zhang et al.
Hodgkin’s De Roos 2003 650 cases/1,933 controls 36 cases p=0.14 for heterogeneity 2019a
lymphoma De Roos 2005a 54,315 Estimated 76%
Eriksson et al. 2008 910 cases/1,016 controls Estimated 2%
Hardell et al. 2002 515 cases/1,141 controls 8 cases
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Table 2-6. Summary of Meta-Analyses of Results from Studies Examining Possible Association Between Self-
Reported Use of Glyphosate and Lymphohematopoietic Cancers
Meta-analysisa
Studies included in Number reporting relative risk or hazard ratio
Outcome analysis Number of participants glyphosate use (95% CI) Reference
McDuffie et al. 2001 517 cases/1,506 controls 51 cases
Orsi et al. 2009 244 cases/435 controls 12 cases
B-cell Cocco et al. 2013 2,348 cases/2,462 controls 4 cases/2 controls 2.0 (1.1–3.6) Chang and
lymphoma Eriksson et al. 2008 1,163 cases/1,016 controls Not stated I2=0.0%, p=0.58 for heterogeneity Delzell 2016;
Schinasi and
Leon 2014
Leukemia Brown et al. 1990 578 cases/1,245 controls 15 cases/49 controls 1.0 (0.6–1.5) Chang and
De Roos et al. 2005a 49,211 43 cases I2=0.0%a, p=0.92 for Delzell 2016
Kaufman et al. 2009 180 cases/756 controls 1 case/3 controls heterogeneity
Multiple Brown et al. 1993 173 cases/650 controls 11 cases/40 controls 1.4 (1.0–1.9) Chang and
myeloma De Roos et al. 2005a 19 cases Not stated I2=0.0%, p=0.63 for heterogeneity Delzell 2016
Kachuri et al. 2013 342 cases/1,357 controls 32 cases/131 controls
Orsi et al. 2009 56 cases/456 controls 5 cases/24 controls
Pahwa et al. 2012 32 cases/133 controls Not stated
Sorahan 2015 40,719 24 cases
Multiple Leveque-Morlais et al. 127,282 Estimated 36% mHR 0.87 (0.66–1.15) Leon et al.
myeloma 2015 I2=0.0%, p=0.95 for heterogeneity 2019
Kristensen et al. 1996 137,821 Estimated 38%
Alavanja et al. 1996 51,167 Estimated 83%
Hodgkin’s Karunanayake et al. 2012 316 cases/1,506 controls 38 cases/133 controls 1.1 (0.7–1.6) Chang and
lymphoma Orsi et al. 2009 87 cases/496 controls 6 cases/24 controls I2=0.0%, p=0.36 for heterogeneity Delzell 2016
Diffuse large Eriksson et al. 2008 955 cases/1,016 controls Not stated 1.1 (0.5–2.3) Chang and
B-cell Orsi et al. 2009 456 controls 5 cases/24 controls I2=0.0%, p=0.79 for heterogeneity Delzell 2016
lymphoma
Diffuse large Leveque-Morlais et al. 127,282 Estimated 36% mHR 1.36 (1.00–1.82) Leon et al.
B-cell 2015 I2=0.0%, p=0.48 for heterogeneity 2019
lymphoma Kristensen et al. 1996 137,821 Estimated 38%
Alavanja et al. 1996 51,167 Estimated 83%
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Table 2-6. Summary of Meta-Analyses of Results from Studies Examining Possible Association Between Self-
Reported Use of Glyphosate and Lymphohematopoietic Cancers
Meta-analysisa
Studies included in Number reporting relative risk or hazard ratio
Outcome analysis Number of participants glyphosate use (95% CI) Reference
Diffuse large McDuffie et al. 2001 517 cases/1,506 controls 51 cases/133 controls mOR 1.60 (1.12–2.29) Pahwa et al.
B-cell Cantor et al. 1992 622 cases/1,245 controls 26 cases/49 controls I2 not reported; p=0.08 for 2019
lymphoma Hoar et al. 1986 200 cases/1,005 controls Not stated heterogeneity
Zahm et al. 1990 201 cases/725 controls Undetermined
CLL/SLL Eriksson et al. 2008 955 cases/1,016 controls Not stated 1.3 (0.2–10) Chang and
Orsi et al. 2009 456 controls 2 cases/18 controls I2=83.7%, p=0.01 for Delzell 2016
heterogeneity
CLL/SLL Leveque-Morlais et al. 127,282 Estimated 36% mHR 0.92 (0.69–1.24) Leon et al.
2015 I2=0.0%, p=0.38 for heterogeneity 2019
Kristensen et al. 1996 137,821 Estimated 38%
Alavanja et al. 1996 51,167 Estimated 83%
CLL/SLL McDuffie et al. 2001 517 cases/1,506 controls 51 cases/133 controls mOR 1.77 (0.98–3.22) Pahwa et al.
Cantor et al. 1992 622 cases/1,245 controls 26 cases/49 controls I2 not reported; p=0.04 for 2019
Hoar et al. 1986 200 cases/1,005 controls Not stated heterogeneity
Zahm et al. 1990 201 cases/725 controls Undetermined
Follicular Eriksson et al. 2008 955 cases/1,016 controls Not stated 1.7 (0.7–3.9) Chang and
lymphoma Orsi et al. 2009 456 controls 3 cases/24 controls I2=0.0%, p=0.73 for heterogeneity Delzell 2016
Follicular Leveque-Morlais et al. 127,282 Estimated 36% mHR 0.79 (0.52–1.21) Leon et al.
lymphoma 2015 I2=0.0%, p=0.56 for heterogeneity 2019
Kristensen et al. 1996 137,821 Estimated 38%
Alavanja et al. 1996 51,167 Estimated 83%
Follicular McDuffie et al. 2001 517 cases/1,506 controls 51 cases/133 controls mOR 1.00 (0.65–1.54) Pahwa et al.
lymphoma Cantor et al. 1992 622 cases/1,245 controls 26 cases/49 controls I2 not reported; p=0.04 for 2019
Hoar et al. 1986 200 cases/1,005 controls Not stated heterogeneity
Zahm et al. 1990 201 cases/725 controls Undetermined
Hairy cell Orsi et al. 2009 456 controls 2 cases/18 controls 2.5 (0.9–7.3) Chang and
leukemia Nordstrom et al. 1998 111 cases/400 controls 4 cases/5 controls I2=0.0%, p=0.63 for heterogeneity Delzell 2016
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Table 2-6. Summary of Meta-Analyses of Results from Studies Examining Possible Association Between Self-
Reported Use of Glyphosate and Lymphohematopoietic Cancers
Meta-analysisa
Studies included in Number reporting relative risk or hazard ratio
Outcome analysis Number of participants glyphosate use (95% CI) Reference
aI 2 is a measure of total variance explained by study heterogeneity and measure of inconsistency in results; higher values indicate greater inconsistency.
2. HEALTH EFFECTS
Leon et al. (2019) performed meta-analyses for exposure to glyphosate with NHL, diffuse large B-cell
lymphoma, chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL), multiple myeloma,
Hodgkin’s lymphoma, and follicular lymphoma based on three cohort studies included in the AGRICOH
consortium; this includes agricultural workers in France, Norway, and the US. Of these, a significant
association was observed between diffuse B-cell lymphoma and glyphosate (meta hazard ratio [HR] 1.36;
95% CI 1.00–1.85; I2 = 0%). The authors concluded that associations were statistically null for NHL
(meta HR 0.95’ 95% CI: 0.77-1.18), multiple myeloma (meta HR 0.87; 95% CI: 0.66-1.15), CLL/SLL
(meta HR 0.92; 95% CI: 0.69-1.24), and follicular lymphoma (meta HR 0.79;95% CI: 0.52-1.21).
Findings for other cancer types are listed in Table 2-6.
Pahwa et al. (2019) conducted meta-analyses for exposure to glyphosate with NHL, diffuse large B-cell
lymphoma, CLL/SLL, and follicular lymphoma based on four case-control studies in the US and Canada.
The authors reported a positive association between glyphosate use and NHL (meta odds ratio [OR] 1.43;
95% CI: 1.11, 1.83) and diffuse large B-cell lymphoma (meta OR 1.60; 95% CI: 1.12-2.29). The authors
concluded that associations were statistically null for CLL/SLL (meta OR 1.77; 95% CI: 0.98-3.22) and
follicular lymphoma (meta OR 1.00; 95% CI: 0.65, 1.54).
Epidemiological Studies
A number of case-control and prospective cohort epidemiology studies have examined possible
associations between use of glyphosate-containing compounds and increased cancer risks. Detailed
overviews—including a description of the exposure metric used, the results, and the conclusions and
limitations as reported by the study authors—are presented in Table 2-7 for solid tumor types and Table
2-8 for lymphohematopoietic cancers.
The majority of the studies examined individuals who were occupationally exposed to pesticides and used
self-reported or proxy-reported (ever/never use of glyphosate-containing compounds) use as the marker of
exposure. A few studies examined potential cancer risk among family members (i.e., wife and children)
of pesticide applicators. The cohort studies utilized data on participants from the Agricultural Health
Study, a prospective study of cancer and other health outcomes. The cohort consisted of >89,000 licensed
pesticide applicators and their spouses (52,394 applicators and 32,345 spouses) who were recruited
between 1993 and 1997 from Iowa and North Carolina. Study limitations included self-reported exposure
information, few cases for many of the cancer subtypes, limited information regarding the timing and
duration of exposure, and recall bias.
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Table 2-7. Cancer Outcomes for Solid Tumor-Types in Humans Exposed to Glyphosate-Containing Products
2. HEALTH EFFECTS
Table 2-7. Cancer Outcomes for Solid Tumor-Types in Humans Exposed to Glyphosate-Containing Products
Kidney:
Q4: RR 1.03 (0.66–1.61)
p-trend: 0.95
De Roos et al. 2005a Exposure: Self-reported All cancers: Conclusions: No association
never/ever use of glyphosate. Ever used: RR 1.0 (0.9–1.2) between glyphosate exposure
Prospective cohort study of Cumulative exposure days CED T3: RR 1.0 (0.9–1.1) and all cancer incidence or most
54,315 certified pesticide applicators (CEDs): 1–20 (reference), 21–56, p-trend: 0.57 of the specific cancer subtypes,
(97% male, 97% Caucasian) in Iowa and and 57–2,678 days. IWED T3: RR 0.9 (0.8–1.1) including NHL. A small number
North Carolina (Agricultural Health Study) Intensity weighted exposure days p-trend: 0.35 of cases suggested a positive
to evaluate agricultural exposure to (IWEDs) of 0.1–79.5 (reference), association between multiple
glyphosate and cancer incidence. 79.6–337.1, and 337.2– Lung: myeloma and glyphosate
18,241 units. Ever used: RR 0.9 (0.6–1.3) exposure.
Among 54,315 subjects included in age- CED T3: RR 0.7 (0.4–1.2)
adjusted analyses, 41,035 subjects Outcomes/endpoints: Cancer p-trend: 0.21 Limitations: Self-reported
reported exposure to glyphosate and registry files in Iowa and North IWED T3: RR 0.6 (0.3–1.0) exposure information, few cases
13,280 reported no exposure. Carolina for case identification. p-trend: 0.02 for many of the cancer subtypes,
Incident cases were identified from most applicators were male, there
Number cases (exposed percent) for enrollment to 2001 (median follow- Oral cavity: is no information on timing of
different cancer sites: up time: 6.7 years). Ever used: RR 1.0 (0.5–1.8) pesticide use in relation to
All cancers: 2,088 (73.0%) CED T3: RR 0.8 (0.4–1.7) disease.
Lung: 204 (72.1%) Data analysis: Poisson regression p-trend: 0.66
Oral cavity: 59 (76.3%) analyses for all cancers combined IWED T3: RR 1.0 (0.5–2.3)
Colon: 174 (75.3%) and 12 specific cancer sites (with p-trend: 0.95
Rectum: 76 (77.6%) at least 30 cases).
Pancreas: 38 (76.3%) Adjustments: Age at enrollment, Colon:
Kidney: 63 (73.0%) education, pack-years of cigarette Ever used: RR 1.4 (0.8–2.2)
Bladder: 79 (76.0%) smoking, alcohol consumption, CED T3: RR 0.9 (0.4–1.7)
Prostate: 825 (72.5%) family history of cancer, state of p-trend: 0.54
Melanoma: 75 (84.0%) residency, and co-exposure to IWED T3: RR 1.4 (0.8–2.5)
10 other pesticides (2,4-D, p-trend: 0.10
alachlor, atrazine, metolachlor,
trifluralin, benomyl, maneb, Rectum:
paraquat, carbaryl, and diazinon). Ever used: RR 1.3 (0.7–2.3)
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Table 2-7. Cancer Outcomes for Solid Tumor-Types in Humans Exposed to Glyphosate-Containing Products
Pancreas:
Ever used: RR 0.7 (0.3–2.0)
CED T3: RR 1.3 (0.5–3.6)
p-trend: 0.83
IWED T3: RR 0.5 (0.1–1.9)
p-trend: 0.06
Kidney:
Ever used: RR 1.6 (0.7–3.8)
CED T3: RR 0.7 (0.3–1.6)
p-trend: 0.34
IWED T3: RR 0.5 (0.2–1.0)
p-trend: 0.15
Bladder:
Ever used: RR 1.5 (0.7–3.2)
CED T3: RR 1.2 (0.6–2.2)
p-trend: 0.53
IWED T3: RR 0.8 (0.3–1.8)
p-trend: 0.88
Prostate:
Ever used: RR 1.1 (0.9–1.3)
CED T3: RR 1.1 (0.9–1.3)
p-trend: 0.69
IWED T3: RR 1.1 (0.9–1.3)
p-trend: 0.60
Melanoma:
Ever used: RR 1.6 (0.8–3.0)
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Table 2-7. Cancer Outcomes for Solid Tumor-Types in Humans Exposed to Glyphosate-Containing Products
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Table 2-7. Cancer Outcomes for Solid Tumor-Types in Humans Exposed to Glyphosate-Containing Products
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Table 2-7. Cancer Outcomes for Solid Tumor-Types in Humans Exposed to Glyphosate-Containing Products
2. HEALTH EFFECTS
Table 2-7. Cancer Outcomes for Solid Tumor-Types in Humans Exposed to Glyphosate-Containing Products
2. HEALTH EFFECTS
Table 2-7. Cancer Outcomes for Solid Tumor-Types in Humans Exposed to Glyphosate-Containing Products
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Table 2-7. Cancer Outcomes for Solid Tumor-Types in Humans Exposed to Glyphosate-Containing Products
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Table 2-7. Cancer Outcomes for Solid Tumor-Types in Humans Exposed to Glyphosate-Containing Products
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Table 2-7. Cancer Outcomes for Solid Tumor-Types in Humans Exposed to Glyphosate-Containing Products
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Table 2-7. Cancer Outcomes for Solid Tumor-Types in Humans Exposed to Glyphosate-Containing Products
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Table 2-7. Cancer Outcomes for Solid Tumor-Types in Humans Exposed to Glyphosate-Containing Products
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Table 2-7. Cancer Outcomes for Solid Tumor-Types in Humans Exposed to Glyphosate-Containing Products
Randomly-selected, population-based
controls were frequency-matched within a
state.
BMI = body mass index; CED = cumulative exposure day; CI = confidence interval; IWED = intensity weighted exposure day; JEM = job exposure matrix;
NHL = non-Hodgkin’s lymphoma; OR = odds ratio; RR = relative risk; Q = quartile; STS = soft tissue sarcoma; T = tertile
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BMI = body mass index; CED = cumulative exposure day; CI = confidence interval; CLL/SLL = chronic lymphocytic leukemia/small lymphocytic lymphoma;
DLBCL = diffuse large B-cell lymphoma; HCL = hairy cell leukemia; IWED = intensity weighted exposure day; M = median; NHL = non-Hodgkin’s lymphoma; OR =
odds ratio; Q = quartile; RR = relative risk; T = tertile; WHO = World Health Organization
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Solid Tumors. The epidemiological studies on the association between glyphosate use and solid-type
tumors are presented in Table 2-7. Overall, these studies did not detect a statistically significant
association between glyphosate use and all cancer types studied, including melanoma, childhood cancers,
soft tissue sarcoma, colorectal cancer, and cancers of the lung, oral cavity, colon, rectum, pancreas,
kidney, prostate (including total prostate and aggressive prostate cancers), testes, breast, bladder, stomach,
and esophagus. A statistically significant association with glyphosate use and solid tumors was reported
in one study. Lee et al. (2005) reported an association between proxy-reported glyphosate use and glioma
cancer (odds ratio [OR] 3.1; 95% CI 1.2–8.2). However, when using self-reported glyphosate use or
combined self- and proxy-reported glyphosate use, no association with glioma was observed (OR 0.4;
95% CI 0.1–1.6 and OR 1.5; 95% CI 0.7–3.1, respectively).
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Sheppard and Shafer (2019) is theoretically possible, however based on a sensitivity analysis, Andreotti
et al. argue their imputation likely did not impact risk estimates.
In contrast, Eriksson et al. (2008) reported positive associations between glyphosate use and lymphocytic
lymphoma (OR 2.56; 95% CI 1.17–5.60) and unspecified NHL (OR 5.29; 95% CI 1.60–17.50). Several
other studies reported significant associations between glyphosate use and NHL, but these studies reported
conflicting results depending on the statistical methods used, adjustment for confounders, or inclusion
criteria. De Roos et al. (2003) reported a positive association between glyphosate use and NHL using
logistic regression (OR 2.1; 95% CI 1.1–4.0); however, analysis using hierarchical regression did not find
an association (OR 1.6; 95% CI 0.9–2.8). Similarly, Eriksson et al. (2008) reported a positive association
with NHL (OR 2.02; 95% CI 1.10–3.71); when this analysis further adjusted for other pesticide use, the
reported OR was 1.51 (95% CI 0.7–2.94). Hardell et al. (2002) investigated the association between
glyphosate use and combined cases of NHL and hairy cell leukemia. The authors reported an OR of
3.04 (95% CI 1.08–8.52) in unadjusted models, but after adjusting for potential confounders, the reported
OR was 1.85 (95% CI 0.55–6.20). McDuffie et al. (2001) reported that glyphosate use was not associated
with NHL (OR 1.20; 95% CI 0.83–1.74); however, after restricting analyses to individuals who reported
using glyphosate >2 days a year, there was a positive association with NHL (OR 2.12; 95% CI 1.20–3.73).
Results for risk of non-Hodgkin’s lymphoma and self-reported glyphosate use or exposure from
individual studies summarized in Table 2-8 and meta-analyses summarized in Table 2-6 are plotted in
Figure 2-4. Results for risk of multiple myeloma and self-reported glyphosate use or exposure from
individual studies summarized in Table 2-8 and the meta-analysis summarized in Table 2-6 are plotted in
Figure 2-5.
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a = adjusted; CED = cumulative exposure; IWED = intensity-weighted exposure days; IWLD = intensity-weighted
lifetime days; OR = odds ratio; Q4 = 4th quartile; RR = rate ratio; T3 = 3rd tertile
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*Set 1 included 54,315 applicators; **Set 2 included 49,211 applicators; ***Set 3 included 40,719 applicators; ****Set
4 included 55,934 applicators
a = adjusted; CED = cumulative exposure; IWED = intensity-weighted exposure days; IWLD = intensity-weighted
lifetime days; IRED = intensity-rated exposure days; OR = odds ratio; Q4 = 4th quartile; RR = rate ratio; T3 = 3rd tertile
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EPA evaluated results from four unpublished rat studies in which the carcinogenicity of glyphosate
technical was assessed; EPA summarized the findings in publicly available DERs (EPA 1991a, 1991b,
1992d, 2015c).
Groups of weanling Sprague-Dawley rats (50/sex/group) were administered glyphosate technical (98.7%
purity) in the diet for up to 26 months at initial concentrations of 0, 30, 100, or 300 ppm (EPA 1992d).
Based on body weight and food consumption data, concentrations of glyphosate technical were adjusted
to achieve oral doses of 0, 3.05, 10.30, and 31.49 mg/kg/day, respectively, for males and 0, 3.37, 11.22,
and 34.02 mg/kg/day, respectively, for females. Incidences of testicular interstitial cell tumors in the
control, low-, mid-, and high-dose male rats were 0/50 (0%), 3/50 (6%), 1/50 (2%), and 6/50 (12%),
respectively (Table 2-9). The incidence in the high-dose males was statistically significant (p=0.013) in
pairwise comparison to the control incidence. Although the incidence in the mid-dose group was less
than that in the low-dose group, trend analysis revealed a significant trend (p=0.009) for increasing
incidence of testicular interstitial cell tumors with increasing dose. Evaluation of historical control
incidences resulted in testicular interstitial cell tumor incidences in the range of 0–12%, with a mean
incidence of 4.5% (range: 3.4–6.7%) among lifetime studies that employed the same rat strain and were
conducted concurrently with the 26-month study.
Incidences of thyroid c-cell tumors (adenoma, carcinoma, combined adenoma or carcinoma) in the female
rats are presented in Table 2-9. An increased incidence of thyroid c-cell carcinomas in female rats
approached statistical significance (p=0.055) at the highest dose (6/47 versus 1/47 for controls) (EPA
1992d). The combined incidence of combined c-cell carcinomas or adenomas was not significantly
increased (9/47 high-dose females versus 6/47 controls), and time-to-tumor analysis revealed no sign of a
treatment-related effect. Historical control incidences of spontaneous thyroid c-cell tumors in female
Sprague-Dawley rats were as high as 17%.
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aSignificantly different from concurrent control according to Fisher’s Exact Test (p<0.05).
Groups of albino Sprague-Dawley rats (60/sex/group) were administered technical glyphosate (96.5%
purity) in the diet at target concentrations of 0, 2,000, 8,000, or 20,000 ppm (mean measured
concentrations of 0, 1,900, 7,600, and 19,000 ppm, respectively) for up to 24 months (EPA 1991a,
1991b). Based on mean body weight and food consumption data, estimated glyphosate doses to controls
and low-, mid-, and high-dose groups were 0, 89, 362, and 940 mg/kg/day, respectively, for the males and
0, 113, 457, and 1,183 mg/kg/day, respectively, for the females.
As shown in Table 2-10, low-dose (but not mid- or high-dose) males exhibited significantly increased
incidences of pancreatic islet cell adenoma (p=0.015) in pairwise comparison to control incidence (EPA
1991a, 1991b). Incidences of pancreatic islet cell carcinoma in low-, mid-, and high-dose males were not
significantly different from control incidences. Incidences of combined adenoma or carcinoma among
mid-, and high-dose males were not significantly different from control incidences. After excluding those
male rats that died or were sacrificed prior to treatment week 55 (before the first adenoma or carcinoma
were observed), incidences of pancreatic islet cell adenoma in the low-dose group remained significantly
(p=0.018) higher than controls. However, exclusion of the early deaths resulted in only borderline
significantly increased incidence of combined adenoma or carcinoma (p=0.052) in the low-dose group.
Historical control incidences for pancreatic islet cell adenoma in male rats from 2-year studies conducted
at the same testing facility ranged from 1.8 to 8.5%. In the female rats, no significant differences were
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observed between controls and treated rats regarding pancreatic islet cell tumor incidences in pairwise
comparisons with controls.
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aSignificantly different from concurrent control according to Fisher’s Exact Test (p<0.05).
bMarginally significantly different from concurrent control according to Fisher’s Exact Test (p=0.051).
cSignificant trend (p<0.05) for increasing incidence of adenoma and adenoma/carcinoma combined, excluding
As shown in Table 2-10, the incidence of thyroid c-cell adenoma in mid-dose (but not low- or high-dose)
male rats was marginally significantly (p=0.051) greater than that of controls. Historical control
incidences for thyroid c-cell adenoma in male rats ranged from 1.8 to 10.6%. Pairwise comparison with
concurrent controls revealed no significant difference between controls and low-, mid-, or high-dose
groups regarding incidences of thyroid c-cell adenoma or carcinoma. There were no significant
differences between controls and low-, mid-, or high-dose groups regarding incidences of thyroid c-cell
adenoma after excluding those male rats that died prior to week 54 (EPA 1991a, 1991b). In the female
rats, no significant differences were observed between controls and treated rats regarding thyroid c-cell
tumor incidences in pairwise comparisons with controls. Significant trends (p<0.05) for increasing
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incidence of adenoma and adenoma/carcinoma combined were noted after excluding those female rats
that died prior to week 55 (EPA 1991a, 1991b).
As shown in Table 2-10, incidences of liver tumors in the glyphosate-treated male rats were not
significantly different from incidences among controls. Lack of statistical significance remained after
excluding those rats that died or were sacrificed prior to study week 55 and upon combining incidences of
adenoma or carcinoma combined.
EPA summarized results from two unpublished rat studies in which the carcinogenicity of glyphosate
technical was assessed. In one study, groups of Alpk:APfSD Wistar rats (64/sex/group) received
glyphosate (97.6% purity) from the diet for up to 2 years at 0, 121, 361, or 1,214 mg/kg/day (males) and
0, 145, 437, or 1,498 mg/kg/day (females) (EPA 2015c). An interim sacrifice was performed on
12 rats/sex/group after 1 year. Incidences of hepatocellular adenoma among controls, low-, mid-, and
high-dose male rats were reported as 0/52 (0%), 2/52 (4%), 0/52 (0%), and 5/52 (10%), respectively. The
incidence in the high-dose group was significantly greater than that of controls (p=0.028 by Fisher’s exact
test). EPA (2015c) noted a range of 0–11.5% for this tumor type among historical controls reported by
Greim et al. (2015). In the other study, there were no treatment-related increased incidences of any tumor
type among Sprague-Dawley rats (50/sex/group) that received glyphosate (98.9 purity) from the diet for
up to 104 weeks at 0, 100, 300, or 1,000 mg/kg/day (EPA 2015c).
EPA also evaluated results from two unpublished mouse studies in which the carcinogenicity of
glyphosate technical was assessed; EPA summarized the findings in publicly-available DERs.
In one study, groups of CD-1 mice (50/sex/group) were administered technical glyphosate (99.78%
purity) for 24 months at doses of 0, 161, 835, or 4,945 mg/kg/day to the males and 0, 195, 968, or
6,069 mg/kg/day to the females (EPA 2015a; selected results also available in EPA 1985a, 1985b, 1986b,
1989, and 1993). Guidelines for testing of chemicals for carcinogenicity generally consider
1,000 mg/kg/day as an upper limit for oral dosing (e.g., OECD Test Guideline 451, available at:
http://www.oecd.org/chemicalsafety/testing/41753121.pdf). The highest dose tested in the mouse study
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far exceeds the upper limit and the mid-dose level approached the upper limit. There were no treatment-
related effects on tumor incidences in the female mice. Table 2-11 shows incidence data for renal tubular
cell tumors in the male mice summarized by EPA (2015a). There were no statistically significant trends
for increased incidence of renal tubule adenoma, carcinoma, or combined carcinoma or adenoma and no
statistically significant differences between groups upon pairwise analyses.
Table 2-11. Incidences of Renal Tubular Cell Tumors in Male CD-1 Mice
Administered Technical Glyphosate (99.78% Purity) in the Diet for
up to 24 Months
Dose (mg/kg/day)
0 161 835 4,945
Adenoma 1/49 (2%) 0/49 (0%) 0/50 (0%) 1/50 (2%)
Carcinoma 0/49 (0%) 0/49 (0%) 1/50 (2%) 2/50 (4%)
Adenoma or carcinoma (combined) 1/49 (2%) 0/49 (0%) 1/50 (2%) 3/50 (6%)
In the other study, groups of CD-1 mice (50/sex/group) received glyphosate (≥97.5% purity) from the diet
at 0, 100, 300, or 1,000 mg/kg/day for 104 weeks (EPA 2015c). Incidence data for tumors reported by
EPA are summarized in Table 2-12. Compared to controls, the incidence of hemangiosarcoma in the
high-dose males approached the level of statistical significance (p=0.056 according to Fishers exact test).
A significant trend (p=0.00296) was noted for increased incidence of hemangiosarcoma with increasing
dose. All tumors were malignant and were located in the liver and spleen of one mouse; liver of another
mouse; spleen of a third mouse; and liver, spleen, and prostate of the fourth mouse. Hemangiosarcoma
incidences among glyphosate-treated female mice were not significantly increased relative to controls.
All tumors were malignant and were located in the uterus of one low-dose female, spleen of another low-
dose female, and liver of the high-dose female.
Table 2-12. Incidences of Tumors in Male and Female CD-1 Mice Administered
Glyphosate (≥97.5% Purity) in the Diet for up to 104 Weeks
Dose (mg/kg/day)
0 100 300 1,000
Males
Hemangiosarcoma 0/50a (0%) 0/50 (0%) 0/50 (0%) 4/50 (8%)
Histiocytic sarcoma 0/50 (0%) 2/50 (4%) 0/50 (0%) 2/50 (4%)
Females
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Table 2-12. Incidences of Tumors in Male and Female CD-1 Mice Administered
Glyphosate (≥97.5% Purity) in the Diet for up to 104 Weeks
Dose (mg/kg/day)
0 100 300 1,000
Hemangiosarcoma 0/50 (0%) 2/50 (4%) 0/50 (0%) 1/50 (2%)
Histiocytic sarcoma 0/50 (0%) 3/50 (6%) 3/50 (6%) 1/50 (2%)
Additional studies were conducted evaluating the potential carcinogenicity and pathogenic role of
glyphosate or glyphosate formulation in cancer, specifically multiple myeloma. George et al. (2010)
evaluated the potential carcinogenicity of Roundup Original® using the 2-stage mouse skin
carcinogenesis model. The study included groups of male Swiss albino mice (20/group) receiving the
glyphosate formulation topically 3 days/week for 32 weeks, single topical application of
dimethylbenz[a]anthracene (DMBA; a tumor initiator) followed by repeated dermal applications of
12-O-tetradecanoyl-phorbol-13-acetate (TPA; a tumor promoter), single or multiple topical application of
the glyphosate formulation followed by dermal applications of TPA (test for initiation potential of the
glyphosate formulation), single application of DMBA followed by repeated dermal application of the
glyphosate formulation (test for promotion potential of the glyphosate formulation), single DMBA
application, repeated TPA application, and untreated controls. Skin tumors were observed in 100% of the
DMBA + TPA treatment group; the first tumor appeared at 52 days. Tumors were noted in 40% of the
DMBA + glyphosate formulation treatment group; the first tumor appeared at 130 days. No tumors were
observed in other groups. The results indicate that the glyphosate formulation functioned as a tumor
promoter, but not a tumor initiator or complete carcinogen.
In an effort to understand whether glyphosate is involved in the pathogenesis of multiple myeloma, Wang
et al. (2019) treated wild type and multiple myeloma model mice (C57b1/b strain) with drinking water
containing up to 30 g/L glyphosate for 7 days or 1.0 g/L of glyphosate for 72 weeks. Vk*MYC mice with
sporadic MYC activation in germinal B cells have been found to be the best available animal model for
multiple myeloma (MM); this model follows the biological and clinical progression of human multiple
myeloma. In the acute study, neither spleen, body weight nor serum creatinine levels were altered,
however, plasma cells in bone marrow, spleen and lymph nodes were elevated (Wang et al. 2019). In the
chronic study of 72 weeks, Wang et al. (2019) observed glyphosate to damage the liver and kidney and
induce splenomegaly and benign monoclonal gammopathy in wildtype (WT) mice, an early indicator of
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MM in humans; in MM model mice, glyphosate was seen to cause splenomegaly and organ dysfunction
including lytic bone lesions, renal, liver, lung and kidney damage. Glyphosate also promoted the
progression of multiple myeloma in Vk*MYC mice as shown by the development of plasma cell
neoplasms. Upregulation of activation-induced cytidine deaminase (AID), a B-cell genome mutator, in
bone marrow and spleen was exhibited in wild type and MM model mice in both acute and chronic study
duration (Wang et al. 2019).
Assessment of Carcinogenicity. Several national and international agencies and organizations have
assessed the carcinogenicity of glyphosate (Table 2-13). These evaluations provide different types of
determinations—some focused on hazard identification, or whether there is evidence that a chemical can
cause an effect, and others focused on carcinogenic risk, or the likelihood of cancer effects at levels of
exposure typically experienced by humans. In addition, there are large numbers of unpublished guideline
studies on glyphosate and the inclusion or exclusion of these may account for the differences in the
conclusions reached by these various agencies. For additional discussion regarding the carcinogenicity of
glyphosate, refer to the following sources: Acquavella et al. 2016; Greim et al. 2015; McClellan 2016;
Portier et al. 2016; Samsel and Seneff 2015; Tarazona et al. 2017; Williams et al. 2016.
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2.20 GENOTOXICITY
The potential genotoxicity of glyphosate technical and glyphosate formulations has been extensively
evaluated. The intent of this section of the Toxicological Profile for Glyphosate is to present
representative results from available sources of information on glyphosate technical and glyphosate
formulations. Results from selected in vitro and in vivo genotoxicity tests for glyphosate technical are
presented in Table 2-14 and Table 2-15, respectively. Results from selected in vitro and in vivo
genotoxicity tests for glyphosate formulations are presented in Table 2-16 and Table 2-17, respectively.
Result
Test
substance Activation
Species (test system) purity Endpoint With Without Reference
Salmonella typhimurium NS Gene mutation – – EPA 1992i
TA98, TA100, TA1535,
TA1537
S. typhimurium TA98, NS Gene mutation – – Kubo et al. 2002
TA100
S. typhimurium TA97a, NS Gene mutation – – Chruscielska et al.
TA98, TA100, TA102 2000
S. typhimurium TA98, 98% Gene mutation – – Li and Long 1988
TA100, TA1535,
TA1537, TA1538
S. typhimurium TA97, 98.6% Gene mutation – – NTP 1992
TA98, TA100, TA1535
Escherichia coli WP2 98% Gene mutation – – Li and Long 1988
hcr
Chinese hamster ovary 98% Gene mutation – – Li and Long 1988
cells
Bacillus subtilis rec+, 98% rec assay NT – Li and Long 1988
rec-
Human peripheral blood >98% Chromosomal aberrations NT + Lioi et al. 1998a
lymphocytes
Bovine peripheral blood ≥98% Chromosomal aberrations NT + Lioi et al. 1998b
lymphocytes
Human peripheral blood >96% Chromosomal aberrations NT – Mañas et al. 2009
lymphocytes
Human peripheral blood >98% Sister chromatid exchange NT (+) Lioi et al. 1998a
lymphocytes
Human peripheral blood 99.9% Sister chromatid exchange NT + Bolognesi et al.
lymphocytes 1997
Bovine peripheral blood ≥98% Sister chromatid exchange NT (+) Lioi et al. 1998b
lymphocytes
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Result
Test
substance Activation
Species (test system) purity Endpoint With Without Reference
Human-derived buccal 95% Micronuclei NT + Koller et al. 2012
epithelial cells
Chinese hamster CHO- NS Micronuclei – + Roustan et al. 2014
K1 cells
Rat hepatocytes 98% Unscheduled DNA NT – Li and Long 1988
synthesis
Human fibroblast 96% DNA damage NT + Alvarez-Moya et al.
CM5757 cells 2014
Human fibroblasts 98.4% DNA damage NT + Lueken et al. 2004
Human peripheral blood 96% DNA damage NT + Mañas et al. 2009
lymphocytes
Human GM38 cells Technical DNA damage NT + Monroy et al. 2005
grade
Human HT1080 Technical DNA damage NT + Monroy et al. 2004,
(fibrosarcoma) cells grade 2005
Chinese hamster ovary Technical DNA damage NT + Monroy et al. 2004
cells grade
Raji cells 95% DNA damage NT + Townsend et al.
2017
Human lymphocytes NS DNA damage NT + Suarez-Larios et al.
2017
Human lymphocytes NS Chromosomal aberrations NT + Santovito et al. 2018
Human lymphocytes NS Micronuclei NT + Santovito et al. 2018
Peripheral blood NS DNA damage NT + Kwiatkowska et al.
mononuclear cells 2017
HEPG2 Standard DNA damage NT + Kasuba et al. 2017
purity
<100%
HEPG2 Standard Micronuclei NT + Kasuba et al. 2017
purity
<100%
HEC1A 99.5% DNA damage NT + De Almeida et al.
2018
MDA MB 231 99.5% DNA damage NT + De Almeida et al.
2018
MCF7 99.5% DNA damage NT - De Almeida et al.
2018
Mouse (oocytes) NS DNA Damage NT + Zhang et al. 2019b
Mouse (oocytes) NS Abnormal chromosome + Zhang et al. 2019b
spindle
– = negative result; + = positive result; (+) = weakly positive result; +/– = equivocal result; DNA = deoxyribonucleic
acid; NS = not specified; NT = not tested
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Test
substance
Species (test system) purity Endpoint Result Reference
Oral exposure
Mouse (bone marrow) 98.6% Micronuclei – NTP 1992
Mouse (male germ cells) 98.7% Dominant lethal mutation – EPA 1992j
Intraperitoneal injection
Rat (bone marrow) 98% Chromosomal aberrations – Li and Long 1988
Mouse (bone marrow) 99.9% Micronuclei + Bolognesi et al. 1997
Mouse (bone marrow) 96% Micronuclei + Mañas et al. 2009
Mouse (bone marrow) NSa Micronuclei – Rank et al. 1993
Mouse (liver DNA) 99.9% DNA damage + Bolognesi et al. 1997
Mouse (kidney DNA) 99.9% DNA damage + Bolognesi et al. 1997
Mouse (liver DNA) 99.9% Oxidative DNA damage + Bolognesi et al. 1997
Mouse (kidney DNA) 99.9% Oxidative DNA damage – Bolognesi et al. 1997
Mouse (liver, kidney DNA) NSa DNA adducts – Peluso et al. 1998
Rats (leukocytes, liver ≤100 % DNA damage + Milic et al. 2018
DNA)
Result
Glyphosate Activation
Test system formulation End point With Without Reference
Salmonella typhimurium Roundup® Gene mutation – – Moriya et al. 1983
TA98, TA100, TA1535, (composition NS)
TA1537, TA1538
S. typhimurium TA98 Roundup® (48% Gene mutation – (+)a Rank et al. 1993
glyphosate
isopropylamine salt)
S. typhimurium TA100 Roundup® (48% Gene mutation (+)b – Rank et al. 1993
glyphosate
isopropylamine salt)
S. typhimurium TA98, Glyphosate Gene mutation – – Wildeman and
TA100 (Unspecified Nazar 1982
commercial
formulation)
Escherichia coli WP2 hcr Roundup® Gene mutation – – Moriya et al. 1983
(composition NS)
GLYPHOSATE 131
2. HEALTH EFFECTS
Result
Glyphosate Activation
Test system formulation End point With Without Reference
Bovine peripheral blood Glyphosate (62% Chromosomal NT – Holečková 2006
lymphocytes w/w isopropylamine aberrations
salt; 38% unspecified
inerts)
Bovine peripheral blood Glyphosate (62% Chromosomal NT – Šiviková and
lymphocytes isopropylamine salt; aberrations Dianovskỳ 2006
38% unspecified
inerts)
Human peripheral blood Roundup® (not Sister chromatid NT (+) Vigfusson and
lymphocytes otherwise described) exchange Vyse 1980
Human peripheral blood Roundup® (30.4% Sister chromatid NT + Bolognesi et al.
lymphocytes glyphosate) exchange 1997
Bovine peripheral blood Glyphosate (62% Sister chromatid + + Šiviková and
lymphocytes isopropylamine salt; exchange Dianovskỳ 2006
38% unspecified
inerts)
Human-derived buccal Roundup Ultra Max® Micronuclei NT + Koller et al. 2012
epithelial cells (45% glyphosate)
Bovine peripheral blood Glyphosate (62% Micronuclei NT (+) Piešová 2004
lymphocytes isopropylamine salt;
38% unspecified
inerts)
Bovine peripheral blood Glyphosate (62% Micronuclei NT (+) Piešová 2005
lymphocytes isopropylamine salt;
38% unspecified
inerts)
Human liver HepG2 cells Grands Travaux® DNA damage NT (+) Gasnier et al. 2009
(40% glyphosate)
E. coli PQ37 Roundup BIO® (NS) DNA damage NT + Raipulis et al. 2009
HEC1A Roundup DNA damage NT + De Almeida et al.
2018
MDA MB 231 Roundup DNA damage NT + De Almeida et al.
2018
MCF7 Roundup DNA damage NT - De Almeida et al.
2018
HEC1A Wipeout DNA damage NT + De Almeida et al.
2018
MDA MB 231 Wipeout DNA damage NT + De Almeida et al.
2018
MCF7 Wipeout DNA damage NT - De Almeida et al.
2018
peripheral blood Roundup DNA damage NT + Wozniak et al.
mononuclear cells 2018
GLYPHOSATE 132
2. HEALTH EFFECTS
Result
Glyphosate Activation
Test system formulation End point With Without Reference
aWeakly positive at 360 μg/plate in one test (4-fold increase in revertants/plate) but not in another test; cytotoxicity at
concentrations ≥360 μg/plate.
bWeakly positive at 720 μg/plate (3.3-fold increase in revertants/plate); cytotoxicity at concentrations ≥360 μg/plate.
– = negative result; + = positive result; (+) = weakly positive result; NS = not specified; NT = not tested
Test substance
Species (test system) (purity) End point Result Reference
Drosophila (sex-linked Roundup® (glyphosate Gene mutation + Kale et al. 1995
recessive lethal isopropylamine salt;
mutation assay)a purity NS)
Oral
Mouse (bone marrow) Roundup® (9.8% active Chromosomal – Dimitrov et al. 2006
ingredient) aberrations
Intraperitoneal injection
Mouse (bone marrow) Roundup® (>41% Chromosomal + Prasad et al. 2009
glyphosate aberrations
isopropylamine salt)
Mouse (bone marrow) Roundup® (48% Micronuclei – Rank et al. 1993
glyphosate
isopropylamine salt)
Mouse (bone marrow) Roundup® (30.4% Micronuclei + Bolognesi et al. 1997
glyphosate)
Mouse (bone marrow) Roundup® (9.8% Micronuclei – Dimitrov et al. 2006
glyphosate)
Mouse (bone marrow) Roundup® (>41% Micronuclei + Prasad et al. 2009
glyphosate
isopropylamine salt)
Mouse (bone marrow) Roundup® (48% Micronuclei – Grisolia 2002
glyphosate
isopropylammonium
salt; 12% inerts
including POEA)
Mouse (liver DNA) Roundup® (30.4% DNA damage + Bolognesi et al. 1997
glyphosate)
Mouse (kidney DNA) Roundup® (30.4% DNA damage + Bolognesi et al. 1997
glyphosate)
Mouse (liver DNA Roundup® (30.4% Oxidative DNA – Bolognesi et al. 1997
glyphosate) damage
Mouse (kidney DNA) Roundup® (30.4% Oxidative DNA + Bolognesi et al. 1997
glyphosate) damage
GLYPHOSATE 133
2. HEALTH EFFECTS
Test substance
Species (test system) (purity) End point Result Reference
Mouse (liver, kidney Roundup® (30.4% DNA adducts + Peluso et al. 1998
DNA) glyphosate
isopropylammonium
salt)
Glyphosate Technical. Glyphosate did not induce gene mutations either with or without exogenous
metabolic activation in numerous bacterial assays, or in assays using mammalian cells (Chruscielska et al.
2000; EPA 1992i, Kubo et al. 2002; Li and Long 1988; NTP 1992). Lioi et al. (1998a, 1998b) reported
concentration-related significant increases in chromosomal aberrations in human and bovine peripheral
blood lymphocytes exposed to glyphosate, although concomitant decreases in mitotic index were
indicative of some degree of cytotoxicity at least at the highest glyphosate concentrations. Mañas et al.
(2009) found no evidence of glyphosate-induced chromosomal aberrations in human peripheral blood
lymphocytes. Glyphosate was positive for induction of sister chromatid exchange in one assay using
human peripheral blood lymphocytes (Bolognesi et al. 1997); weakly positive responses were obtained in
other assays using human lymphocytes (Lioi et al. 1998a) and bovine lymphocytes (Lioi et al. 1998b).
There was some evidence of cytotoxicity in the assays of Lioi et al. (1998a, 1998b). The result was
considered equivocal due to significant apoptosis at concentrations resulting in significantly increased
micronuclei frequency. Koller et al. (2012) reported significantly increased frequency of micronuclei in
an assay using human-derived buccal epithelial cells exposed to glyphosate. Roustan et al. (2014)
reported significantly increased micronuclei frequency in Chinese hamster ovary K1 cells exposed to
glyphosate without (but not with) exogenous metabolic activation. Negative results were obtained in an
assay that evaluated the potential for glyphosate to induce unscheduled DNA synthesis in rat hepatocytes
(Li and Long 1988). Mañas et al. (2009) and Lueken et al. (2004) reported positive results for DNA
damage in glyphosate-exposed human fibroblasts. Alvarez-Moya et al. (2014) reported DNA damage in
human fibroblast CM5757 cells exposed to glyphosate technical. Exposure-related DNA damage was
observed in assays of human GM38 cells (Monroy et al. 2005), human HT1080 (fibrosarcoma) cells
(Monroy et al. 2004, 2005), and Chinese hamster ovary cells (Monroy et al. 2004) exposed to glyphosate
technical.
GLYPHOSATE 134
2. HEALTH EFFECTS
Townsend et al (2017) evaluated DNA damage in human Raji cells exposed to various concentrations of
glyphosate. Significant DNA damage occurred after exposure to concentrations of 1 or 5 mM for 30 to
60 minutes. However, after two hours, DNA damage was no longer apparent. One hour after the initial
exposure, cells were again exposed to the same concentrations for the same length of time. DNA repair
was not observed in any cells after two exposures (Townsend et al. 2017). Suarez-Larios et al (2017) also
reported DNA damage in the form of double strand breaks in human lymphocytes after exposure to
glyphosate. Santovito et al (2018) reported increases in chromosomal aberrations, micronuclei, and
nuclear microplasmic bridges with increasing doses of glyphosate in human lymphocytes. Kwiatkowska
et al (2017) also reported DNA damage in the form of single and double stand breaks in human
lymphocytes after exposure to glyphosate. However, after two hours, significant repair of the DNA had
occurred. The authors also reported a significant decrease in DNA methylation levels.
DNA damage was also reported in HEPG2 cells after 4 hours of exposure but not after 24 hours of
exposure (Kasuba et al. 2017). Kasuba et al (2017) also report statistically significant increases in
micronuclei and nuclear buds after four hours of exposure. Increases were also reported for
nucleoplasmic bridges, but not at statistically significant levels after four hours of exposure. After 24
hours of exposure, decreases in micronuclei and nucleoplasmic bridges were noted (Kasuba et al. 2017).
De Almeida et al (2018) also reported DNA damage in two of three cell lines assessed: HEC1A and MDA
MB 231. No significant damage was reported for the MCF7 cell line. Wozniak et al (2018) reported
DNA damage for human peripheral blood mononuclear cells after exposure to glyphosate for 24 hours.
Elie-Caille et al. (2010) examined the effects of glyphosate on human keratinocyte cell lines and found
alterations in cell morphology and size that were indicative of apoptosis.
Koureas et al. (2014) investigated the effects of occupational exposures to pesticides on oxidative DNA
damage. Use of herbicides (defined as glyphosate, ammonium or glufosinate) was significantly associated
with increased risk of oxidative damage, as measured by levels of 8-hydroxy-2-deoxyguanosine in whole
blood (RR = 2.60; 95% CI: 1.35-5.04). However, no significant associations were found between levels
of this marker and glyphosate exposure specifically (RR = 1.47; 95% CI: 0.78-2.77).
Zhang et al. (2019b) reported DNA damage in the form of double strand breaks as well as abnormal
spindly morphology in mouse oocytes after exposure to up to 500 µM glyphosate for 14h. See section
2.16 for a discussion of non-genotoxic reproductive effects associated with glyphosate exposure.
GLYPHOSATE 135
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The genotoxicity of glyphosate technical has been evaluated in a number of in vivo tests; results are
mixed across a variety of cell types. Glyphosate did not induce dominant lethal mutations following oral
dosing of male CD-1 mice once by gavage at up to 2,000 mg/kg (EPA 1992j). Glyphosate did not
increase the frequency of micronuclei in bone marrow cells from B6C3F1 mice administered glyphosate
in the diet for 13 weeks at concentrations resulting in estimated doses as high as 10,780–
11,977 mg/kg/day (NTP 1992). Glyphosate did not increase the frequency of micronuclei in bone
marrow cells from C3H mice administered glyphosate technical via single intraperitoneal injection
(Chruscielska et al. 2000) or NMRI-bom mice administered glyphosate (as isopropylammonium salt) via
two intraperitoneal injections 24 hours apart (Rank et al. 1993). Glyphosate did not induce chromosomal
aberrations in bone marrow cells from rats administered glyphosate via intraperitoneal injection at
1,000 mg/kg (Li and Long 1988). Kier and Kirkland (2013) summarized results from 10 industry studies
that evaluated frequency of micronuclei in bone marrow cells from mice or rats administered glyphosate
orally or via intraperitoneal injection; results were consistently negative for glyphosate-induced
micronuclei, although an inconclusive result was determined for one study.
However, other investigators reported positive results for micronuclei induction in bone marrow cells
from mice administered glyphosate via intraperitoneal injection by single 300 mg/kg dose (Bolognesi et
al. 1997) or two 200 mg/kg doses 24 hours apart (Mañas et al. 2009). Bolognesi et al. (1997) reported
significantly increased frequency of DNA damage (single strand breaks) in liver and kidney and
significantly increased frequency of oxidative DNA damage in liver (but not kidney) from mice
administered glyphosate via single intraperitoneal injection at 300 mg/kg. Peluso et al. (1998) found no
evidence of the formation of DNA adducts in liver or kidney from mice following intraperitoneal
injection of glyphosate (as isopropylammonium salt) at up to 270 mg/kg. It should be noted that
intraperitoneal injection studies typically employed lethal dose levels; a positive result at such high dose
levels does not necessarily indicate potential for genotoxicity at doses relevant to human exposure. Rats
exposed up to 10 mg/kg bw/day glyphosate orally for 28 days were reported to have DNA damage in
leukocytes and liver cells compared to controls (Milic et al. 2018). Furthermore, liver cell DNA damage
was greatest in the lowest (0.1 mg/kg bw/day) and highest (10 mg/kg bw/day) exposure groups (Milic et
al. 2018).
DNA damage in human fibroblast cells and peripheral blood lymphocytes were the most frequently
reported clearly positive results from available in vitro assays that employed glyphosate technical. From
available in vivo assays that employed glyphosate technical, DNA damage in mouse kidney and liver was
GLYPHOSATE 136
2. HEALTH EFFECTS
the most frequent positive result. Summaries should be interpreted with caution because the genotoxicity
of glyphosate technical was assessed based on a limited number of primary results available to ATSDR.
2. HEALTH EFFECTS
mononuclear cells after exposure to Roundup 360 plus for 24 hours at a dose two orders of magnitude
lower than glyphosate. De Almeida et al (2018) also reported DNA damage in two of three cell lines
exposed to Roundup and Wipeout: HEC1A and MDA MB 231. No significant damage was reported for
the MCF7 cell line.
Several studies were designed to evaluate the genotoxicity of selected glyphosate formulations in vivo;
similar to findings from in vivo studies using glyphosate technical, mixed results were obtained from in
vivo exposure to glyphosate-containing products. Roundup® induced mutations in Drosophila in a sex-
linked recessive lethal mutation assay (Kale et al. 1995). Roundup® did not induce chromosomal
aberrations or micronuclei in mice administered the test chemical orally at a 1,080 mg/kg dose, reported
by the study authors as one-half the LD50 (Dimitrov et al. 2006). The potential for Roundup® to induce
chromosomal aberrations and/or micronuclei in bone marrow cells has been assessed in several studies in
which the test chemical was administered to mice via intraperitoneal injection. Although intraperitoneal
administration of Roundup® at 25 and 50 mg/kg resulted in significantly increased frequencies of
chromosomal aberrations and micronuclei, both doses appeared to be cytotoxic, as indicated by time- and
dose-related significant decreases in mitotic indices (Prasad et al. 2009). Roundup® induced micronuclei
in bone marrow from mice administered the chemical via intraperitoneal injection at 300 mg/kg
(expressed as glyphosate) (Bolognesi et al. 1997). Negative results were reported in two other studies that
evaluated micronucleus induction in bone marrow cells from mice treated by intraperitoneal injection of
Roundup® (Grisolia 2002; Rank et al. 1993). In the study of Grisolia (2002), polyoxyethylene amine
surfactant accounted for 12% of the formulation. Negative results were also reported for micronucleus
induction in bone marrow cells from mice treated by intraperitoneal injection of a commercial
formulation identified only as Perzocyd 10 SL (Chruscielska et al. 2000). Roundup® induced single-
strand breaks in DNA from liver and kidney of mice administered the chemical via intraperitoneal
injection at 300 mg/kg (expressed as glyphosate) and oxidative DNA damage in kidney (but not liver)
cells (Bolognesi et al. 1997). However, Heydens et al. (2008) repeated the study design of Bolognesi et
al. (1997) and found a 300 mg/kg intraperitoneally-injected dose to be highly toxic to liver and kidney. It
was suggested that the genotoxic effects observed by Bolognesi et al. (1997) might have been secondary
effects mediated by local toxicity. Peluso et al. (1998) reported the formation of DNA adducts in liver
and kidney from mice following intraperitoneal injection of Roundup® at doses in the range of 122–
182 mg active ingredient/kg. The DNA adduct formation was considered likely related to other
components of the Roundup® formulation because DNA adduct formation was not observed in mice
similarly treated with analytical-grade glyphosate at 270 mg/kg.
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2. HEALTH EFFECTS
Exposure to glyphosate-containing products and evidence of genetic damage was reported in limited
human studies that did not measure specific exposure levels. Paz-y-Miño et al. (2007) evaluated
prevalence of DNA strand breaks in blood samples from 24 residents of an area in northern Ecuador at 2
weeks to 2 months following aerial applications of Roundup-Ultra®; the study included 21 unexposed
control individuals. The exposed individuals exhibited a higher degree of DNA damage (comet length
35.5±6.4 µm) than the unexposed controls (comet length 25.94±0.6 µm). There was no evidence of
exposure-related chromosomal damage among 92 individuals from 10 communities near the northern
Ecuador border evaluated at 2 years following the last aerial applications of glyphosate-containing
herbicides (Paz-y-Miño et al. 2011). Bolognesi et al. (2009) reported increases in micronuclei in
peripheral blood lymphocytes from nearby residents following aerial spraying of glyphosate-based
formulation with adjuvant to coca and poppy crops, or without adjuvant on sugar-cane plantations. These
residents were evaluated both prior to and following aerial spraying.
DNA damage in human cells was the most frequently reported clearly positive results from available in
vitro assays that employed glyphosate formulations. However, comparison of results across available
studies was precluded due to lack of information regarding the composition of the various formulations
tested. From available in vivo assays that employed glyphosate formulations, DNA damage in mouse
kidney and liver was the most frequent positive result. Summaries should be interpreted with caution
because the genotoxicity of glyphosate technical was assessed based on a limited number of primary
results available to ATSDR.
Additional unpublished genotoxicity assays were submitted to EPA and/or the European Commission
(EC) during re-registration of products containing glyphosate. Many agencies, organizations, and/or
expert panels have reviewed available genotoxicity data and concluded that the data do not support a
genotoxicity role for glyphosate, at least at concentrations relevant to human exposure (e.g., APVMA
2017; Brusick et al. 2016; EFSA 2015; EPA 2017c; FAO and WHO 2016; Health Canada 2017; Kier and
Kirkland 2013; NZ EPA 2016; Williams et al. 2016). In contrast, IARC (2017) concluded that there is
strong evidence for the genotoxicity of glyphosate. For more detailed information regarding genotoxicity
evaluations and conclusions of these agencies, organizations, and/or expert panels, consult corresponding
references.
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2. HEALTH EFFECTS
Mechanism of Action in Plants. Glyphosate-based herbicides act on the shikimate pathway in plants by
blocking the activity of the enzyme, 5-enolpyruvylshikimate-3-phosphate synthetase (EPSPS), thereby
inhibiting the biosynthesis of essential aromatic amino acids in plants (see Funke et al. 2006; Martinez et
al. 2018; Pollegioni et al. 2011 for more specific information regarding mechanisms of action). The
action of glyphosate on the shikimate pathway is not of direct human concern because this pathway does
not exist in mammals. However, animal exposures to glyphosate could impact the shikimate pathway of
gut bacteria, thereby affecting the gut microbiome (Aitbali et al. 2018; Deschartres et al. 2019; Lozano et
al. 2018). The implications of microbiome effects are further discussed in Section 3.1.3.
Some crop plants have been genetically modified to resist the action of glyphosate by the addition of a
glyphosate-insensitive form of EPSPS (CP4 EPSPS) obtained from Agrobacterium sp. strain CP4 (Funke
et al. 2006). Some transgenic plants have been genetically altered to express N-acetyltransferase proteins
(e.g., glyphosate acetyltransferase [GAT4601] from Bacillus licheniformis), which acetylate glyphosate to
a non-phytotoxic metabolite (N-acetylglyphosate) (Pioneer 2006).
Proposed Mechanisms of Action with Human Relevance. Although glyphosate is generally considered
to be of relatively low toxicity to mammals, the following mechanisms of action have been proposed:
Hepatotoxicity. Ford et al. (2017) administered glyphosate to male C57BL/6 mice by intraperitoneal
injection at 200 mg/kg/day for 7 days, after which livers were evaluated for levels of glyphosate,
aminomethylphosphonic acid (AMPA), and glyoxylate (a reactive substance produced endogenously).
Glyphosate treatment at this high dose level resulted in measurable levels of AMPA, indicating some
degree of glyphosate metabolism. Glyphosate treatment also resulted in an approximately 2-fold increase
in glyoxylate. Because glyoxylate is formed endogenously, the increase in glyoxylate level in the liver
may be a result of glyphosate acting on mechanisms responsible for endogenous production of glyoxylate.
The study authors demonstrated that glyoxylate inhibited liver fatty acid oxidation enzymes in mice and
that glyphosate treatment increased triglycerides and cholesteryl esters, which was considered a likely
result of the diversion of fatty acids toward lipid pathways other than oxidation. In another study, Astiz et
al. 2009 exposed rats to 10 mg/kg/bw of glyphosate three times a week for five weeks via injection and
measured oxidative stress and cell damage. In the liver, lipid peroxidation as measured by thiobarbituric
acid-reactive substances (TBARS) was two times greater than control; antioxidant (alpha-Tocopherol)
and SOD levels were significantly decreased suggestive of oxidative damage induced by glyphosate.
GLYPHOSATE 140
2. HEALTH EFFECTS
Enzyme levels of γ-glutamyl transpeptidase, a sensitive biomarker for hepato-cellular damage, increased
by 125% compared to controls indicating glyphosate induces cell damage. No clinical signs of animal
toxicity were observed during the experiment. An in vitro assessment of Roundup® cytotoxicity on
human L-02 hepatocytes determined that exposure induced structural and morphological changes in cell
membranes, mitochondria and nuclei, in addition to cell shrinkage, nuclear fragmentation, and
mitochondrial vacuolar degenerations (Luo et al. 2017). Study authors determined that the Roundup-
induced overproduction of reactive oxygen species led to oxidative stress responses affecting normal cell
function.
Renal toxicity. Mohamed et al. (2016) observed increases in serum and urinary cystatin C and urinary
interleukin-18, cytochrome C, and neutrophil gelatinase-associated protein (NGAL) in patients presenting
with poisoning from glyphosate-based formulations. The study authors noted that the increases in
cystatin C and interleukin-18 suggest that glyphosate-based formulations might induce apoptosis and
mitochondrial toxicity.
Astiz et al. 2009 reported increases in oxidative stress in the kidney tissues of rats exposed to 10
mg/kg/bw day glyphosate as measured by TBARS and a decrease in superoxide dismutase activity (SOD)
level. Dedeke et al. (2018) administered glyphosate alone or a glyphosate-based formulation to rats by
daily gavage for 12 weeks at dose levels of 3.6, 50.4, or 248.8 mg glyphosate/kg/day. The rats
administered the glyphosate-based formulation exhibited significantly altered markers of kidney changes
(serum urea and creatinine, plasma cystatin-C, NGAL), oxidative stress, and activities of selected
membrane-bound enzymes compared to the rats treated with glyphosate alone. Those rats administered
glyphosate-based formulation were the only ones to exhibit severe histopathologic kidney lesions. The
study authors suggested that these results did not support a nephrotoxic role for glyphosate alone.
Dermal Toxicity. George and Shukla (2013) examined whether the mechanism of action for glyphosate
and its potentially tumor-promoting properties could be elucidated; previously the research group found
glyphosate to cause tumor promotion in mouse skin carcinogenesis (George et al. 2010). In an in-vitro
model, human skin keratinocyte, or HaCaT cells, were exposed to up to 1 mM of glyphosate for 72 hours.
Glyphosate was observed to induce proliferation, decrease Ca+2 and increase reactive oxygen species
(ROS) generation in HaCaT cells. Taken together, these suggest glyphosate may possibly have a
proliferative effect on HaCaT cells by disturbing the homeostasis levels of Ca+2 and decrease SOD1 to
increase ROS generation potentially leading to neoplastic growth in the mammalian skin system.
GLYPHOSATE 141
2. HEALTH EFFECTS
Gehin et al. (2005) evaluated the cytotoxic effect of glyphosate or glyphosate formulation (Roundup 3®
plus) in relation to antioxidants such as Vitamin C and E, glyphosate formulation was found to be more
toxic than glyphosate after epidermal HaCaT cells were exposed to the herbicide for 24 hours. Taken
together, glyphosate-based formulations, and comparatively to a lesser degree, glyphosate, are implicated
in generating oxidative damage, which in turn may lead to dermal toxicity. The interaction between
glyphosate and other chemicals (e.g. surfactants) may explain this observation; Section 3.4 discusses this
further.
Neurotoxicity. Astiz et al. 2009 reported increases in oxidative stress in the brain of rats exposed to 10
mg/kg/bw day glyphosate as measured by increased concentrations of TBARS, altered levels of
antioxidant enzymes (decrease in superoxide dismutase and increase in catalase activity), and nitric oxide
metabolites.
Cattani et al. (2014) added 1% Roundup® (0.38% glyphosate) to the drinking water of rat dams from
gestation day 5 through lactation day 15. Hippocampal slices from 15-day-old pups were exposed to
Roundup® (0.00005–0.1%) for 30 minutes. The study authors reported that Roundup® treatment
resulted in increased Ca2+ influx via activation of NMDA receptors and voltage-dependent Ca2+ channels,
activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated
kinase (ERK), increased glutamate release into the synaptic cleft, decreased glutathione content, increased
lipoperoxidation, decreased glutamate uptake and metabolism, and induced Ca2+ uptake and methyl-
amino-isobutyric acid accumulation. The study authors suggested that exposure to Roundup® might lead
to excessive extracellular glutamate levels and resulting glutamate excitotoxicity and oxidative stress in
rat hippocampus.
Martinez and Al-Ahmad (2019) examined the effects of glyphosate on the blood brain barrier in vitro on
induced pluripotent stem cells (iPSCs) after a single exposure. The study used a range of concentrations
similar to levels found in patients and occupational exposures. Following treatment of 1 to 10 µM
glyphosate for 24 hours, there was increased blood brain barrier permeability to fluorescein (dye)
indicating disruption of the barrier function. Glyphosate permeated across the blood brain barrier via a
transcellular mechanism. Subsequently, neuronal cell metabolic activity and glucose uptake in brain
microvascular endothelial cells was observed. Study authors suggest that exposure to glyphosate may lead
to increased blood brain barrier permeability and alteration of glucose metabolism resulting in
neurological damage.
GLYPHOSATE 142
2. HEALTH EFFECTS
Reproductive/endocrine effects. Perego et al. (2017) reported results from an in vitro study designed to
evaluate the effects of glyphosate treatment (up to 5 µg/mL) on bovine granulosa cells and theca cells.
Granulosa cell proliferation and estradiol production were impaired, but no effects were observed on
theca cell proliferation or steroidogenesis. The results suggest that glyphosate may affect the
reproductive system in cattle via direct action on ovarian function. EPA evaluated results from the battery
of in vitro assays and relevant laboratory mammalian and wildlife studies. Using this approach, EPA
determined that there is no convincing evidence of potential interaction between glyphosate and estrogen
or androgen.
Zhang et al. (2019b) evaluated the effects of glyphosate on mice oocytes, and found reduced rates of
germinal vesicle breakdown (GVBD) and first polar body extrusion (PBE), indicating disruption of
nuclear oocyte maturation after treatment with 500 µm glyphosate. In response to glyphosate exposure,
cells produced excess reactive oxygen species, displayed abnormal spindle morphology, DNA double
strand breaks, aggregated distribution of mitochondria and decrease in membrane potential of oocytes.
Genes related to oxidative-stress (cat, sod2, gpx) were found expressed at greater levels than the control
group; on the other hand, expression of apoptosis related genes including Bcl-2 (inhibits apoptosis)
decreased, while Bax (pro-apoptosis gene), increased. Zhang et al. (2019b) suggests these changes led to
the generation of oxidative stress and early apoptosis that result in the interference of mouse oocyte
maturation and development.
Romano et al. (2010) reported decreased serum testosterone in young male rats gavaged with Roundup
Transorb®. Romano et al. (2012) implicated disruption of gonadotropin expression as a mechanism of
action.
Vanlaeys et al. (2018) evaluated the effects of Roundup Bioforce® and Glyphogan on cultured mice TM4
Sertoli cell lines. These formulations induced dose-dependent cell death, and induced cell mitochondrial
dysfunction, lipid droplet accumulation, and disruption of cell detoxification systems. Additionally, the
penetration and accumulation of glyphosate formulants in cells led to cell death. Vanlaeys et al. (2018)
suggests these mechanisms can lead to disruption of reproductive function in pre-pubertal mammals.
Carcinogenicity. As stated in Section 2.20 (Genotoxicity), IARC (2017) concluded that there is strong
evidence for the genotoxicity of glyphosate, although other agencies, organizations, and/or expert panels
have concluded that the data do not support a genotoxicity role for glyphosate (e.g., APVMA 2017;
Brusick et al. 2016; EFSA 2015; EPA 2017c; FAO and WHO 2016; Health Canada 2017; Kier and
GLYPHOSATE 143
2. HEALTH EFFECTS
Kirkland 2013; NZ EPA 2016; Williams et al. 2016). IARC (2017) also concluded that there is strong
evidence for glyphosate-induced oxidative stress based on results from studies of animal models in vivo
and human cells in vitro.
GLYPHOSATE 144
3.1 TOXICOKINETICS
3.1.1 Absorption
Information regarding the toxicokinetics of ingested glyphosate in humans is limited. The detection of
glyphosate in serum and/or urine samples from individuals who had intentionally or unintentionally
GLYPHOSATE 145
Several groups of investigators have evaluated the absorption of glyphosate following oral exposure in
laboratory animals, particularly rats. In one study (NTP 1992), male F344/N rats were administered a
single gavage dose of 14C-glyphosate (purity 99%) in distilled water at 5.6 or 56 mg/kg. Other rats were
administered a single dose of glyphosate at 5.6 mg/kg via intravenous injection, intraperitoneal injection,
or oral (gavage) to compare 24-hour urinary and fecal elimination by these administration routes. Results
from comparative studies of oral, intravenous, and intraperitoneal administration of glyphosate indicated
that urinary radioactivity represented the amount of glyphosate absorbed and fecal radioactivity
represented the amount of unabsorbed glyphosate following oral exposure. Although quantitative data
were not included in the study report, the study authors estimated that 30% of the 5.6 mg/kg dose of
14
C-glyphosate was absorbed and that a slightly higher percentage (34%) of the 56 mg/kg dose was
absorbed. In another study, male Sprague-Dawley rats received a single gavage dose of 12C- and
14
C-glyphosate at 10 mg/kg (Brewster et al. 1991). Based on urinary radioactivity, it was estimated that
35–40% of the oral dose had been absorbed from the gastrointestinal tract. Anadón et al. (2009) reported
an absorption half-life of 2.29 hours following administration of an oral dose of 400 mg glyphosate/kg to
rats; an estimated peak plasma glyphosate of 4.62 μg/mL was reached at 5.16 hours postdosing. Results
from a number of unpublished industry studies cited in EPA (1993), FAO and WHO (2016), IPCS (1994),
and/or Williams et al. (2000), but not available to ATSDR, demonstrate that single or repeated oral dosing
of glyphosate to rats at doses in the range of 10–1,000 mg/kg/day result in urinary excretion of 7–36% of
the administered dose during ≤7 days of posttreatment, which presumably represents the proportion of
absorbed glyphosate.
Limited human data are available regarding the toxicokinetics of glyphosate following dermal exposure.
Increased urinary glyphosate levels among 48 farmer-applicators following application of glyphosate-
containing products is evidence that glyphosate can be absorbed (Acquavella et al. 2004). Dermal
GLYPHOSATE 146
absorption was likely involved in some cases because mean urinary glyphosate was higher among those
farmers (14/48) who did not use rubber gloves.
In vitro studies using human skin samples indicate that dermal penetration of glyphosate is very low.
Wester et al. (1996) applied 300 μL of a 1% aqueous dilution of analytical-grade 14C-labeled glyphosate
to human cadaver skin (0.8 cm2 of available skin area). The study authors reported a permeability
constant of 4.59x10-4 cm/hour, with a lag time of 10.48 hours, which resulted in a calculated flux of
4.12 μg glyphosate/hour. Wester et al. (1991) used a 14C-labeled Roundup® formulation to evaluate
dermal absorption of glyphosate through human skin (in vitro) and abdominal skin of Rhesus monkeys (in
vivo). Undiluted application to human skin samples at doses ranging from 15.4 to 154 μg/cm2 resulted in
0–0.4% dermal absorption over 8 hours postapplication; dermal absorption of glyphosate from aqueous
dilutions of test substance (1:20 or 1:32 test substance:water, v/v) during 16 hours postapplication was
≤2.2%. Twelve-hour in vivo application of the test substance diluted 1:29 with water at concentrations of
25 or 270 μg/cm2 resulted in 7-day recovery of 0.8 and 2.2% of the applied dose, respectively, in the urine
and 3.6 and 0.7%, respectively, in the feces. These results indicate that approximately 3–4% of the
applied dose had been absorbed. An in vitro study using rat skin membranes, applied glyphosate
formulations, concentration and field diluted, for 8 hours at concentrations of 6.249 and 0.08 mg/cm 2 for
MON 35012 and 6.343 and 0.08 mg/cm2 for MON 0139 (van Burgsteden 2002). Over a period of 48
hours, penetration of concentrates was higher, with 10% penetration of MON 35012 concentrate through
rat skin membrane and 1.3% penetration of MON 0139 concentrate.
3.1.2 Distribution
No human or animal data were located regarding distribution of glyphosate following absorption via the
inhalation exposure route.
Limited human data were located regarding distribution of glyphosate following absorption via the oral
exposure route. Menkes et al. (1991) reported measurable glyphosate in kidney, liver, blood, and brain in
postmortem examination of an individual who had ingested 200–250 mL of Roundup®.
GLYPHOSATE 147
Following oral administration, absorbed glyphosate is readily distributed and rapidly eliminated without
significant accumulation in any particular tissue. In male F344/N rats administered a single gavage dose
of 14C-glyphosate (purity 99%) in distilled water at 5.6 or 56 mg/kg, peak blood radioactivity occurred at
1 and 2 hours postdosing, respectively, mean peak blood concentration was 30-fold higher in the high-
dose group (NTP 1992). Among rats gavaged at 5.6 mg radiolabeled glyphosate/kg and evaluated for
tissue distribution, total tissue radioactivity amounted to approximately 12, 11.7, 5.5, 0.9, and 0.1% of the
administered dose at 3, 6, 12, 24, and 96 hours postdosing, respectively. The highest radioactivity level
was found in the small intestine, reaching a peak level of approximately 10% of the administered dose at
6 hours postdosing; radioactivity in the large intestine peaked at approximately 1.2% at 3 hours
postdosing. Liver, kidney, skin, and blood each accounted for <1% of the administered dose at each time
point. By 24 hours postdosing, <1% of the administered dose remained in all tissues combined. Brewster
et al. (1991) administered 12C- and 14C-glyphosate by a single gavage dose at 10 mg/kg to male Sprague-
Dawley rats and found approximately 34% of the administered dose in the small intestine (not associated
with intestinal content) at 2 hours postdosing, decreasing to 0.05% of the administered dose by 96 hours
postdosing. Radioactivity levels in most other tissues (blood, colon, kidney, liver, stomach, abdominal
fat, testicular fat) peaked at 2–6 hours postdosing; each of these tissues accounted for ≤1.3% of the
administered dose at peak and ≤0.06% by 96 hours postdosing. Radioactivity in bone peaked at 6 hours
postdosing (4.7% of the administered dose) and remained at 1.7% at 96 hours postdosing. The tissue to
blood ratio for bone increased with time suggesting a slower elimination from bone compared to blood.
Anadón et al. (2009) reported an absorption half-life of 2.29 hours following administration of an oral
dose of 400 mg glyphosate/kg to rats; an estimated peak plasma glyphosate level of 4.62 μg/mL was
reached at 5.16 hours postdosing.
No human data were located regarding distribution following dermal exposure to glyphosate.
Limited animal data are available. The observation of radioactivity in urine and feces collected from
rhesus monkeys following dermal application of a 14C-labeled Roundup® formulation is demonstration of
systemic distribution following dermal absorption (Wester et al. 1991). However, at sacrifice 7 days
posttreatment, no radioactivity was detected in spleen, ovaries, kidney, brain, abdominal fat, bone
marrow, upper spinal column, or central nervous system fluid.
GLYPHOSATE 148
Limited data are available regarding the distribution of parenterally administered glyphosate. Male and
female Sprague-Dawley rats were administered 14C-glyphosate via intraperitoneal injection at
1,150 mg/kg (EPA 1992h). Radioactivity measured in bone marrow samples taken 30 minutes
postinjection amounted to approximately 0.0044 and 0.0075% of the administered activity for the males
and females, respectively. Anadón et al. (2009) administered glyphosate (95% purity) to male Wistar rats
via intravenous injection at 100 mg/kg. Plasma levels of glyphosate and its metabolite, AMPA, were
measured using high-performance liquid chromatography (HPLC). Reported fast plasma distribution
(half-life of 0.345 hours) and high volume of distribution at steady state (2.99 L/kg) were interpreted to
indicate that glyphosate was extensively distributed to extravascular tissues.
3.1.3 Metabolism
Glyphosate does not undergo significant metabolism in mammals. Available data are limited to the oral
exposure route and indicate that ingested glyphosate is eliminated mostly as parent compound; only a
small amount may be metabolized to AMPA. Figure 3-1 depicts the chemical structures of glyphosate
and AMPA. In one human case of intentional ingestion of an herbicide in a suicide attempt, glyphosate
and its metabolite, AMPA, were detected in serum and urine (Hori et al. 2003). At 16 hours
postingestion, serum levels of glyphosate and AMPA were 4.4 and 0.03 μg/mL, respectively (147:1,
glyphosate:AMPA). Total urinary excretion of glyphosate and its metabolite during 4 days postingestion
was 3.7 g and 25 mg, respectively (148:1, glyphosate:AMPA).
O O
O HO
HO H
P N P NH2
OH
HO HO
Results from available animal studies also indicate that very little ingested glyphosate is metabolized.
Anadón et al. (2009) administered glyphosate (95% purity) to male Wistar rats by gavage at 400 mg
glyphosate/kg. Plasma glyphosate peaked at 5.16 hours postdosing and measured 4.62 μg/mL; plasma
AMPA peaked at 2.42 hours postdosing and measured 0.416 μg/mL. Based on the ratios between the
GLYPHOSATE 149
area under the curve (AUC) for AMPA and the AUC for glyphosate, it was estimated that the metabolite
represented 6.49% of the parent compound plasma concentration. In an unpublished study summarized
by EPA (1993) and Williams et al. (2000), following oral administration of radiolabeled glyphosate
(>99% purity) to Sprague-Dawley rats at 10 mg/kg, the glyphosate metabolite (AMPA) was detected in
the urine (0.2–0.3% of the administered dose) and feces (0.2–0.4% of the administered dose). The
formation of AMPA was thought to have occurred in the gastrointestinal tract (possibly by microflora)
because AMPA was not detected in other rats administered glyphosate via intravenous injection.
Following a single gavage dose of administered radiolabeled glyphosate (>99% purity) to Sprague-
Dawley rats, expired air accounted for <0.27% of the administered radioactivity at 24 hours postdosing,
indicating that glyphosate metabolism had occurred to a slight extent (EPA 1993).
In addition to its potential role in glyphosate metabolism, gut microflora can also be impacted by
exposure to glyphosate and glyphosate-based herbicides. Though the shikimate pathway is absent in
mammals, the shikimate pathway in animal gut microbes synthesizes amino acids (Aitbali et al. 2018;
Nielsen et al. 2018). Rodents orally exposed to doses of glyphosate-based herbicides ranging from 5 to
500 mg/kg/d showed a significant decrease in bacteria count and changes in community composition
(Aitbali et al. 2018; Dechartres et al. 2019). A study using fecal samples from Roundup®-exposed
Sprague-Dawley rats also found changes in bacterial community composition (Lozano et al. 2018).
Decreases in bacteria count were also observed in rodents orally exposed to 5 mg/kg/d of glyphosate
technical (Aitbali et al. 2018). However, fecal samples from Sprague-Dawley rats orally exposed to doses
of glyphosate or Glyfonova® found that while minimal changes in bacteria composition were observed,
exposure to the glyphosate formulation appeared to have a more pronounced effect than exposure to
glyphosate technical (Nielsen et al. 2018). While the implications of alterations in the gut microbiome are
unclear, some animal studies suggest neurologic and behavioral changes (Aitbali et al. 2018; Dechartres
et al. 2019; Lozano et al. 2018) and greater susceptibility to infection may be associated with loss of
microbiome diversity, especially in cases of malnutrition (Nielsen et al. 2018; Shehata et al. 2013).
Ford et al. (2017) administered glyphosate to male C57BL/6 mice by intraperitoneal injection at
200 mg/kg/day for 7 days. Glyphosate treatment at this high dose level resulted in measurable levels of
AMPA (approximately 4% of the dose of glyphosate) and an approximately 2-fold increase in hepatic
glyoxylate (a reactive substance produced endogenously). Because glyoxylate is formed endogenously,
the increase in glyoxylate level in the liver may be a result of glyphosate acting on mechanisms
responsible for endogenous production of glyoxylate.
GLYPHOSATE 150
3.1.4 Excretion
Limited information is available regarding elimination and excretion of glyphosate in humans following
inhalation exposure. In one study, urinary glyphosate levels were evaluated in 48 farmer-applicators prior
to application of glyphosate-containing products, immediately following application, and for 3 days
thereafter (Acquavella et al. 2004). Urinary glyphosate was detectable in 15% (7/47) of the farmers prior
to application, in 60% (29/48) of the farmers immediately following application, and in only 27% (13/48)
of the farmers on postapplication day 3. No information was located regarding elimination or excretion
following inhalation exposure of laboratory animals to glyphosate.
Roberts et al. (2010) estimated a half-life of 3–4 hours for elimination of glyphosate from the blood of
patients who had intentionally ingested large amounts of glyphosate-containing herbicide products. In
other cases of poisoning victims, plasma glyphosate levels dropped rapidly (within 2–3 days) following
the onset of observation (e.g., Talbot et al. 1991). Glyphosate has been detected in feces and urine of
individuals who intentionally or accidentally ingested relatively large amounts of glyphosate.
Results from animal studies identify the feces and urine as major routes of elimination following oral
exposure to glyphosate. For example, among male and female Sprague-Dawley rats administered
14
C-glyphosate (99% purity) via a single gavage dose at 10 mg/kg, during 7 days posttreatment,
radioactivity recovered in the feces averaged 62.4 and 69.4% of the administered dose (males and
females, respectively); another 28.6 and 22.5% of the administered dose (males and females, respectively)
was recovered in the urine (IPCS 1994). Thus, feces and urine accounted for approximately 88–91% of
the administered dose. HPLC analysis revealed that parent compound accounted for 98.5–99.3% of the
radioactivity in feces and urine. There were no significant differences in fecal and urinary excretion
among rats dosed with unlabeled glyphosate for 14 days followed by a single oral dose of radiolabeled
glyphosate. Following a single gavage dosing of 14C-glyphosate (>96% purity) to male and female
Sprague-Dawley rats at 30 mg/kg, the feces accounted for 57–59% of the administered radioactivity and
the urine accounted for 27–29% during the first 36 hours posttreatment; indicating that fecal and urinary
excretion occur relatively rapidly following oral exposure to glyphosate (IPCS 1994). In male F344/N
rats administered a single gavage dose of 14C-glyphosate (purity 99%) in distilled water at 5.6 or 56
mg/kg, 72-hour collection of feces and urine resulted in the recovery of 91–92% of the administered
GLYPHOSATE 151
radioactivity; 74 and 19%, respectively, at the low dose and 58 and 34%, respectively, at the high dose
(NTP 1992). In one study (NTP 1992), male F344/N rats were administered a single dose of glyphosate
at 5.6 mg/kg via intravenous injection, intraperitoneal injection, or oral (gavage) to compare 24-hour
urinary and fecal elimination by these administration routes. Results from comparative studies of oral,
intravenous, and intraperitoneal administration of glyphosate indicated that urinary radioactivity
represented the amount of glyphosate absorbed and fecal radioactivity represented the amount of
unabsorbed glyphosate following oral exposure. Although quantitative data were not included in the
study report, the study authors estimated that 30–34% of the oral doses of 14C-glyphosate was absorbed
and excreted in the urine. Therefore, approximately 66–70% was unabsorbed and eliminated in the feces.
Very little ingested glyphosate is eliminated via routes other than feces and urine. Among Sprague-
Dawley rats administered radiolabeled glyphosate (>99% purity) by a single gavage dose, <0.27% of the
administered radioactivity was recovered in expired air at 24 hours postdosing (EPA 1993).
No information was located regarding elimination or excretion following known dermal exposure to
glyphosate in humans. However, in a study that evaluated urinary glyphosate levels in 48 farmer-
applicators involved in application of glyphosate-containing products, mean urinary glyphosate was
higher among those farmers (14/48) who did not use rubber gloves, indicating that some glyphosate had
been absorbed through the skin (Acquavella et al. 2004). Limited information is available for laboratory
animals. Wester et al. (1991) applied a 14C-labeled Roundup® formulation to the abdominal skin of
Rhesus monkeys (in vivo) to evaluate dermal absorption of glyphosate. Twelve-hour application of the
test substance at concentrations of 25 or 270 μg/cm2 resulted in 7-day recovery of 0.8 and 2.2% of the
applied dose, respectively, in the urine and 3.6 and 0.7%, respectively, in the feces.
Male and female Sprague-Dawley rats were administered 14C-glyphosate via intraperitoneal injection at
1,150 mg/kg (EPA 1993). Assuming first-order kinetics, the half-life of elimination from the bone
marrow was estimated at 7.6 and 4.2 hours for males and females, respectively. A half-life for
elimination of radioactivity from plasma was approximately 1 hour for both sexes. These results indicate
that glyphosate reaching the blood was rapidly eliminated and that the small fraction reaching bone
marrow was rapidly eliminated. Anadón et al. (2009) reported a half-time of 9.99 hours for elimination of
GLYPHOSATE 152
glyphosate from the blood of male Wistar rats administered glyphosate (95% purity) via intravenous
injection at 100 mg/kg.
PBPK models use mathematical descriptions of the uptake and disposition of chemical substances to
quantitatively describe the relationships among critical biological processes (Krishnan et al. 1994). PBPK
models are also called biologically based tissue dosimetry models. PBPK models are increasingly used in
risk assessments, primarily to predict the concentration of potentially toxic moieties of a chemical that
will be delivered to any given target tissue following various combinations of route, dose level, and test
species (Clewell and Andersen 1985). Physiologically based pharmacodynamic (PBPD) models use
mathematical descriptions of the dose-response function to quantitatively describe the relationship
between target tissue dose and toxic endpoints.
No information was located to suggest significant differences between animals and humans regarding the
toxicokinetics of glyphosate.
This section discusses potential health effects from exposures during the period from conception to
maturity at 18 years of age in humans. Potential effects on offspring resulting from exposures of parental
germ cells are considered, as well as any indirect effects on the fetus and neonate resulting from maternal
exposure during gestation and lactation. Children may be more or less susceptible than adults to health
effects from exposure to hazardous substances and the relationship may change with developmental age.
This section also discusses unusually susceptible populations. A susceptible population may exhibit
different or enhanced responses to certain chemicals than most persons exposed to the same level of these
chemicals in the environment. Factors involved with increased susceptibility may include genetic
makeup, age, health and nutritional status, and exposure to other toxic substances (e.g., cigarette smoke).
These parameters can reduce detoxification or excretion or compromise organ function.
GLYPHOSATE 153
Populations at risk of exposure to glyphosate at unusually high levels are discussed in Section 5.7,
Populations with Potentially High Exposures.
Limited information was located regarding possible age- or gender-related differences in susceptibility to
toxic effects from glyphosate technical or glyphosate formulations. Mao et al. (2018) added glyphosate
or Roundup Bioflow® to the drinking water of rat dams from GD 6 through lactation and to their
offspring up to postpartum day 125 at a concentration resulting in a dose of 1.25 mg glyphosate/kg/day.
Microbiome profiling of the gut resulted in significant changes in overall bacterial composition in the
pups only (particularly apparent prior to puberty); this effect was noted for glyphosate and for Roundup
Bioflow®. Romano et al. (2010) employed Roundup Transorb® as a test substance and found decreased
serum testosterone in young male rats gavaged at a dose as low as 5 mg/kg/day; however, the effect may
have been caused, at least in part, by other ingredients in the glyphosate formulation.
Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have
been classified as biomarkers of exposure, biomarkers of effect, and biomarkers of susceptibility
(NAS/NRC 1989).
Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an
organism that (depending on magnitude) can be recognized as an established or potential health
impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of
tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial
cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung
GLYPHOSATE 154
capacity. Note that these markers are not often substance specific. They also may not be directly
adverse, but can indicate potential health impairment (e.g., DNA adducts formed by covalent bonding of a
chemical to DNA, the formation of which can induce abnormal replication, mutation, and/or prevent
proper DNA repair). Biomarkers of effect caused by glyphosate are discussed in Section 3.3.2.
Glyphosate and the metabolite, AMPA, have been measured in blood and urine (e.g., Connolly et al.
2018; Conrad et al. 2017; Mills et al. 2017; Soukup et al. 2020; Zhang et al. 2020; Zoller et al. 2020;
Zouaoui et al. 2013). However, most absorbed glyphosate is rapidly excreted as parent compound, and
urine is generally considered to be a stronger biomarker of exposure given that the level of detection
(LOD) for glyphosate in urine is much lower than the LOD for glyphosate in blood (see Table 5-4).
Meaningful quantification of exposure would require analysis of blood and/or urine within hours
following exposure, though a case study on glyphosate poisoning reported plasma glyphosate levels over
the course of 2 to 3 days, rather than hours (Talbot et al. 1991).
Information on the toxicological effects of glyphosate interacting with other chemicals such as inert
ingredients is limited. Inert ingredients include other substances that alter the physico-chemical properties
to improve plant absorption or stability of the active ingredient(s) (Defarge et al. 2016). Inert ingredients
include surfactants. Surfactants such as polyethoxylated tallow amine (POEA) in glyphosate-containing
products might enhance the toxicity of glyphosate; results from one study indicate that the surfactant may
be more acutely toxic than glyphosate or the combination of glyphosate and POEA (e.g., Adam et al.
1997). In an in vitro study using three human embryotic cell lines (kidney, liver, and placenta), glyphosate
GLYPHOSATE 155
formulations and formulation additives were found to be more toxic than glyphosate technical alone.
Based on measured cytotoxicity evaluated via mitochondrial respiration, membrane disruption, and
caspases 3/7 activity, the glyphosate formulations were more toxic than glyphosate alone, and the
adjuvants POE-15 and Genamin were more toxic than either the glyphosate formulations or glyphosate
alone (Mesnage et al. 2013).
Increased toxicity of glyphosate formulations compared to glyphosate technical was also observed in
another in vitro study. Defarge et al. (2016) observed in vitro that co-formulants including
polyethoxylated tallow amine (POEA), alkyl polyglucoside (APG), polyoxyethylenealkyl ether phosphate
(POE-APE), quaternary ammonium compound (QAC) and glyphosate formulations (inert and glyphosate
combined) to exert toxic effects far greater than glyphosate alone. Cytotoxicity was determined by
measuring mitochondrial respiration and endocrine disrupting activity was measured by aromatase
activity inhibition. Although, Defarge et al. did not find that glyphosate inhibited mitochondrial
respiration, disturbed cell membranes, or disrupted endocrine activity, co-formulants APG and POAE
were up to 18 times and 200 times more cytotoxic than glyphosate, respectively, and co-formulants and
glyphosate-based herbicide formulations were cytotoxic at concentration 18-2000 times and 8-141 times
lower, than the recommended agricultural dilution of 1%, respectively. In short, co-formulants POEA,
APG, POE-APE, QAC and glyphosate formulation including R classic were found to be more toxic than
the active ingredient glyphosate.
GLYPHOSATE 156
Glyphosate is an organic acid composed of a phosphonomethyl and glycine component. The chemical
name for glyphosate is N-(phosphonomethyl) glycine. Glyphosate is a zwitterion with four distinct
dissociation constants (pKa values are depicted below) and exists as different ionic species depending on
the pH of its surroundings. Glyphosate is an amphoteric chemical and may react as an acid or a base
under certain conditions.
Glyphosate isopropylamine (Chemical Abstracts Registry Number [CASRN] 38641-94-0) is one of the
salt forms of glyphosate used in commercial herbicides employing glyphosate as an active ingredient.
This substance is registered as a pesticide by the EPA (1993) and is used to control broadleaf weeds and
grasses; in food and nonfood settings, flower gardens, lawns, turf, residential areas, and forests; and along
roadsides. Use of glyphosate as a pesticide outside of an agricultural context would be considered non-
agricultural. Some labels may list the active ingredient in a formulation of glyphosate and the acid
equivalents (AE), which is the theoretical yield of the parent acid from the formulated ester or salt. For
example, the AE of glyphosate isopropylamine salts is 74%.
Detailed information on the chemical identity of glyphosate and glyphosate isopropylamine is provided in
Table 4-1.
Detailed information on the physical and chemical properties of glyphosate and glyphosate
isopropylammonium is provided in Table 4-2.
GLYPHOSATE 157
Characteristic Information
Chemical name Glyphosate Glyphosate isopropylamine
Synonym(s) Glyphosphate; N-(phosphonomethyl) Glycine, N-(phosphonomethyl)-, compound
glycine; phosphonomethyliminoacetic with 2-propanamine (1:1); glyphosate-
acid; glyphosate acid isopropylammonium; glyphosate
mono(isopropylamine) salt; glyphosate-
mono(isopropylammonium);
N-(phosphonomethyl)glycine,
isopropylamine salt
Partial list of Pondmaster; Roundup® Max; Roundup®; Rondo; Rodeo; Glifonox; Glycel;
registered trade Glifoglex; Glycel; Muster; Rondo; MON-0139; CP 70139; Shackleb
name(s) Sonic; Spasor; Sting; Tumbleweed;
MON-0573; CP 67573
Chemical formula C3H8NO5P C3H8NO5P.C3H9N
Chemical structure
aAllinformation obtained from McBean (2011), O’Neil et al. (2013), and/or ChemIDplus (2017) unless noted
otherwise.
bEPA 1993.
5.1 OVERVIEW
Glyphosate has not been identified in any of the 1,832 hazardous waste sites that have been proposed for
inclusion on the EPA National Priorities List (NPL) (ATSDR 2015). However, the number of sites
evaluated for glyphosate is not known.
• The general population is exposed to glyphosate via ingestion of crops, plants, and foods with
residues of this chemical. Residential exposure may occur via inhalation, dermal contact, and/or
ocular contact during mixing or application of consumer products containing glyphosate or by
coming into contact with crops, soils, or water to which glyphosate-containing products have
been applied.
• Occupational exposure to glyphosate may occur via inhalation, dermal contact, and/or ocular
contact during manufacture, transport, mixing, loading, application, and disposal processes.
Accidental oral exposure may occur via unintentional ingestion. Dermal contact appears to be
the major route of exposure to glyphosate for individuals involved in its application.
• Glyphosate mainly enters the environment as a direct result of its herbicidal use. Fate of this
chemical in the environment includes degradation, transport, and partitioning processes, which
are governed by its physicochemical properties and by abiotic or biotic degradation under certain
environmental conditions. Glyphosate is a nonvolatile, highly polar, non-residual herbicide that
has low potential for environmental persistence and is unlikely to bioaccumulate.
5.2.1 Production
No information is available in the Toxics Release Inventory (TRI) database on facilities that manufacture
or process glyphosate because this chemical is not required to be reported under Section 313 of the
Emergency Planning and Community Right-to-Know Act (Title III of the Superfund Amendments and
Reauthorization Act of 1986) (EPA 2005b).
Production of glyphosate is achieved through heating phosphorous acid and a-amino acetic acid followed
by the addition of formaldehyde (Muller and Applebyki 2010). Glyphosate may also be produced by
heating glycine and chloromethylphosphonic acid in aqueous sodium hydroxide (IPCS 1994).
GLYPHOSATE 160
Glyphosate is produced commercially in the United States as a technical-grade substance with a purity
≥80%, but usually over 90% (IPCS 1994, McBean 2011).
Glyphosate is typically manufactured for commercial use as a salt available in soluble liquid and soluble
granule formulations. Salt forms of glyphosate include the isopropylamine salt, sodium salt, and
monoammonium salt. Table 5-1 summarizes some of the common glyphosate salts that may be used as
active ingredients in herbicides. Due to the various salt forms, the active ingredient listed on products is
sometimes expressed in terms of acid equivalent.
H3C CH3
aPan 2014
CAS = Chemical Abstracts Service; EPA = U.S. Environmental Protection Agency; PC = pesticide chemical
Herbicide formulations employing glyphosate salts are commonly produced in combination with
additives, inert ingredients, and surfactants. The salt derivatives enhance absorption of glyphosate from
the surface of the plant or leaf structure, but are not the herbicidally active portion of the compound.
Specific formulations vary in composition and are marketed under numerous trade names (NPIRS 2017;
PAN 2009). Polyoxyethylene amine (POEA) (CASRN 24911-53-5) is a surfactant used in the
GLYPHOSATE 161
commercial product Roundup® (PAN 2009). Surfactants are used in herbicide formulations to increase
penetration of glyphosate into plants. Sulfuric acid (CASRN 7664-93-9), phosphoric acid (CASRN 7664-
38-2), propylene glycol (CASRN 57-55-6), and sodium benzoate (CASRN 532-32-1) are examples of
additives used in some formulations (IPCS 1994; PAN 2009). Products may contain other active
ingredients such as simazine (CASRN 122-34-9) and 2-methyl-4-chlorophenoxyacetic acid (CASRN 94-
74-6). The herbicide 2,4-dichlorophenoxyacetic acid (CAS 94-75-7) may also be present at
concentrations ranging from 11.1 to 20.6% (IPCS 1994). Commercial products containing glyphosate
have been reported with concentrations ranging from 0.96 to 94 w/w%. The common herbicide,
Roundup®, has product formulations containing glyphosate concentrations ranging from 0.96% to 71%
(w/w) (NPIRS 2017; PAN 2016b). These products may be diluted depending upon the labeled use as per
manufacturers specifications.
The introduction of glyphosate-resistant crops such as soybeans in 1996, canola and cotton in 1997, and
maize in 1998, along with the distribution of their genetically engineered seeds, had major impacts on the
production and demand for glyphosate.
According to the National Pesticide Information Retrieval System (NPIRS), as of May 2017, there were
43 companies manufacturing EPA federally registered products under the active pesticide code 417300
(glyphosate) (since many chemical names are too long to be handled easily, EPA assigns a 6-digit
chemical code number for every active chemical ingredient), which are available for use in the United
States; see Table 5-2 (NPIRS 2017). In addition, there were 72 companies in the United States that were
manufacturing chemicals under the active pesticide code 103601 (glyphosate isopropylamine salt)
(NPIRS 2017).
5.2.2 Import/Export
5.2.3 Use
Glyphosate is a phosphonoglycine herbicide, first registered for use by the EPA in 1974. In June 1986,
glyphosate was issued a Registration Standard (EPA 1986c) requiring additional data, which included
phytotoxicity, environmental fate, toxicology, product chemistry, and residue chemistry studies;
reregistration of single active ingredient formulations, plus one additional active ingredient formulation,
were finalized in 1993 (EPA 1993). Glyphosate is registered for pre- and post-emergent applications for
weed control in the production of various fruit, vegetable, and field crops. Glyphosate may be applied to
fields prior to planting in order to remove unwanted weeds and vegetation or in preparation for harvesting
in glyphosate resistant crops. Recommended application rates, methods of application and timing,
temperature considerations, etc. may be found on individual product labels. Glyphosate is in the process
of registration review by EPA; docket ID: EPA-HQ-OPP-2009-0361-0066 (EPA 2017c).EPA published
an interim registration review decision in January 2020; docket ID: EPA-HQ-OPP-2009-0361 (EPA
2020), which will be finalized after an EPA Endocrine Disruptor Screening Program FFDCA
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determination, evaluation of glyphosate under the Endangered Species Act, and the resolution of a
petition by the Environmental Working Group.
Glyphosate is used as a non-selective contact herbicide. Formulations are applied directly to control
native and invasive weeds and vegetation around food crops and non-food field crops, and in non-crop
areas such as roadsides, golf courses, right-of-way locations, and aquatic areas. Glyphosate is used in
agriculture, forestry, industrial, lawn and garden, and aquatic (e.g., Rodeo®, Clearcast®) environments
for weed control. In aquatic usage, the formulation typically contains no surfactant or a surfactant that is
nontoxic to aquatic organisms and applications must be made as per the product instructions to avoid
rapid vegetative decay, which can lead to anaerobic environments and potential fish kills (Dow 2017).
Glyphosate is applied to control broad-leaved weeds and woody brush, as well as annual and perennial
grasses (Muller and Applebyke 2010; Plimmer et al. 2004). The sodium salt (CASRN 34494-03-6) can
be used as a plant growth regulator for peanuts and sugarcane (EPA 1993). Glyphosate is a foliar-applied
herbicide. Before the introduction of genetically modified glyphosate-resistant crops, application
generally occurred before crops were planted (Duke and Powles 2008). After successful production and
approval of glyphosate-resistant crops, such as soybean, cotton, maize, and canola, application generally
occurs after planting and before harvest; the timing depends on the specific application (Duke and Powles
2008; Muller and Applebyke 2010). The introduction of these glyphosate-resistant crops increased the
use of herbicidal products containing this chemical because it is possible to use it post-emergence without
actually harming the crop. Greater than 90% of the soybeans produced in the United States are
glyphosate tolerant, and most cotton (72%) and about half of the corn (52%) planted in 2007 were
glyphosate tolerant (Coupe et al. 2012). It has been estimated that genetically engineered glyphosate-
tolerant crops now account for about 56 % of its global usage (Benbrook 2016). Application techniques
include aerial treatments, typically used for large-scale purposes, and wiping equipment or spraying
equipment attached to vehicles, generally used for small-scale applications (FAO 1997; IPCS 1994).
Newer application practices, such as the addition of glyphosate to crops to simplify the harvesting process
(referred to as “green burndown”), may have implications for usage rates of the herbicide (Zhang et al.
2019a).
According to data from the Pesticide Action Network (PAN) Pesticide Database, there are 102 products
containing glyphosate (CASRN 1071-83-6) as the active ingredient, 94 of which have active registrations
in the United States. There are 848 products containing glyphosate isopropylamine salt (CASRN 38641-
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94-0) as the active ingredient, of which 739 have active registrations in the United States (PAN 2016a,
2016b).
Increasing trends in annual agricultural use data for the United States are reflected from the use statistics
available from the U.S. Geological Survey (USGS) National Water-Quality Assessment (NAWQA)
Program. Estimated yearly usage increased from approximately 20 to 60 million pounds from 1992 to
1998, from approximately 70 to 130 million pounds from 1999 to 2003, from approximately 140 to
250 million pounds from 2004 to 2011, and steady use of approximately 285–290 million pounds from
2012 through 2014 (USGS 2017). Figure 5-1 illustrates the agricultural use of glyphosate from 1992 to
2009 in the United States (USGS 2013).
Benbrook (2016) compiled data from the National Agricultural Statistical Service (NASS) to estimate the
amount of glyphosate applied for weed control in the production of major agricultural crops and non-
agricultural (residential uses) in the United States from 1990–2014. The trends are summarized in Table
5-3.
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Crop 1990 Active ingredient (pounds) 2014 Active ingredient (pounds) % Increase
Soybean 2,663,000 122,473,987 4,499.10%
Corn 880,066 68,949,452 7,734.58%
Cotton 192,429 17,421,787 8,953.62%
Wheat (winter) 331,758 12,353,488 3,623.64%
Alfalfa 381,525 8,853,600 2,220.58%
Sorghum 236,305 4,178,573 1,668.30%
Sugar beets 36,130 2,763,075 7,547.59%
Canola 0 219,392 NA
Wheat (spring) 75,308 1,201,807 1,495.86%
Barley 13,1568 1,064,160 708.83%
Other cops 1,897,522 4,526,043 138.52%
Total 7,683,070 249,906,307 3,152.69%
Non-Agricultural Use
5,300,000 26,519,000 400.36%
The EPA recently granted the registration of a new herbicide named Enlist Duo™ containing 2,4-D
choline salt and glyphosate for use on genetically modified corn and soybean crops designed to be
resistant to 2,4-D and glyphosate (EPA 2014).
5.2.4 Disposal
Wastes resulting from products containing glyphosate should be disposed of at an approved waste
disposal facility or in landfills approved for pesticide disposal. Disposal practices should be in
accordance with federal, state, and local procedures. Non-refillable containers should never be reused.
Empty containers should be rinsed thoroughly and offered for recycling, if available, or disposed of in
accordance with container labels. Rinse-water can be emptied into formulation equipment and applied as
residual pesticide in the appropriate manner. Do not contaminate fresh waters when disposing of
equipment wash waters or container rinse waters. Containers that have not been completely rinsed may
be considered hazardous and should be disposed of with regard to federal, state, and local regulations.
Any unused product may be recycled by applying the product in an approved use setting or returning it to
the manufacturer or supplier for safe disposal (Agrisolutions 2010; EPA 1993, 2011).
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TRI data should be used with caution because only certain types of facilities are required to report (EPA
2005b). This is not an exhaustive list. Manufacturing and processing facilities are required to report
information to the TRI only if they employ ≥10 full-time employees; if their facility is included in
Standard Industrial Classification (SIC) Codes 10 (except 1011, 1081, and 1094), 12 (except 1241), 20–
39, 4911 (limited to facilities that combust coal and/or oil for the purpose of generating electricity for
distribution in commerce), 4931 (limited to facilities that combust coal and/or oil for the purpose of
generating electricity for distribution in commerce), 4939 (limited to facilities that combust coal and/or
oil for the purpose of generating electricity for distribution in commerce), 4953 (limited to facilities
regulated under RCRA Subtitle C, 42 U.S.C. section 6921 et seq.), 5169, 5171, and 7389 (limited S.C.
section 6921 et seq.), 5169, 5171, and 7389 (limited to facilities primarily engaged in solvents recovery
services on a contract or fee basis); and if their facility produces, imports, or processes ≥25,000 pounds of
any TRI chemical or otherwise uses >10,000 pounds of a TRI chemical in a calendar year (EPA 2005b).
No information is available in the TRI database on facilities that manufacture or process glyphosate
because this chemical is not required to be reported under Section 313 of the Emergency Planning and
Community Right-to-Know Act (Title III of the Superfund Amendments and Reauthorization Act of
1986) (EPA 2005b).
The use of glyphosate as an herbicide for crops and non-crop applications is the major source of
glyphosate that intentionally enters the environment. Some glyphosate may be released from the
manufacture, transport, and disposal of glyphosate or glyphosate-containing products. The majority of
herbicidal formulations with glyphosate are directly applied to weeds to remove unwanted vegetation in
residential and agricultural settings. Depending on its application, glyphosate may enter aquatic
environments through direct application to control aquatic weeds (Dow 2017) or as a result of overspray
in areas near aquatic environments. Aerial applications of glyphosate may result in unintended transport,
depending on application technique and meteorological conditions, such as wind drift (EPA 1993; IPCS
1994; PAN 2009; Yates et al. 1978).
5.3.1 Air
There is no information on releases of glyphosate to the atmosphere from manufacturing and processing
facilities because these releases are not required to be reported (EPA 2005b).
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Glyphosate released to the air from aerial and ground equipment has the potential for downwind transport.
Yates et al. (1978) assessed the loss due to drift after application. The lowest drift losses resulted when
ground sprayers operating at low pressure were employed. The highest drift losses occurred when jet
nozzles were employed during aerial application performed by helicopter.
The Air Quality System (AQS) database is EPA’s repository of criteria air pollutants and hazardous air
pollutants (HAPs), containing monitoring data from >2,600 monitoring sites across the United States.
Glyphosate has not been included in the AQS ambient air monitoring data as of 2016 (EPA 2017a).
5.3.2 Water
There is no information on releases of glyphosate to water from manufacturing and processing facilities
because these releases are not required to be reported (EPA 2005b).
Glyphosate may enter surface water systems either directly as a result of its aquatic use or indirectly due
to overspray near surface water. Aquatic applications of glyphosate are used to control invasive aquatic
species such as water chestnut (Trapa natans) or other labeled weeds (EPA 2010); however, no
quantitative data are available regarding how much glyphosate is applied to aquatic waterways in the
United States. Glyphosate may also enter surface waters indirectly due to transport of residues in run-off
or erosion events. The amount of glyphosate transported to nearby water bodies from runoff and erosion
is dependent upon several factors, including the frequency, timing, and application rate of glyphosate to
nearby areas, meteorological conditions (e.g., rainfall events and duration), and the characteristics of the
soils in the treated areas. Hydrological factors such as input to the waterbody from overland flow as
compared to subsurface infiltration also effect potential pesticide loadings. Coupe et al. (2012) studied
the glyphosate levels at three locations located in the United States (South Fork River Basin, Iowa; Sugar
Creek River Basin, Indiana; and Bogue Phalia Basin, Mississippi). The basins are located in agricultural
areas dominated by soybean, corn, rice, and cotton (Mississippi only) production, but have differing
climates and soil characteristics. Water samples collected from 2007 to 2008 at three sites located in the
Bogue Phalia basin all had detectable levels of glyphosate and its degradation product,
aminomethylphosphonic acid (AMPA). Glyphosate concentrations at the sites ranged from 0.03 to 73
µg/L. Levels showed a distinctive seasonal pattern with lowest levels occurring in winter, followed by a
steady increase into late fall, which coincided with seasonal application timings of glyphosate. Moreover,
both glyphosate and AMPA loads into the basin were greater in 2008 as compared to 2007, which
corresponded to a higher rainfall rate for that year. Approximately 59–72% of the water samples
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collected from the South Fork River basin had detectable levels of glyphosate ranging from <0.02 to 5.7
µg/L. Higher glyphosate loadings as a percentage of usage into the Bogue Phalia Basin as compared to
the South Fork River Basin is a result of a higher overland flow in the basin (as compared to subsurface
water infiltration) and the fact that the majority of soils in the Bogue Phalia Basin are characterized as
heavy clay soils classified as hydrologic soil groups C and D, which have higher runoff potential than the
predominant soil types in the South Fork River Basin.
Glyphosate levels in the Sugar Creek River Basin, Indiana were limited to measurements taken during
two heavy rainfall storm events in which 2.6 and 5.7 cm of rain were recorded. Glyphosate levels ranged
from 0.16 to 430 µg/L, with the highest level recorded during the heavier rainfall event.
Battaglin et al. (2005) discussed the occurrence of glyphosate in 51 streams in the Midwestern United
States from pre-emergence, post-emergence, and harvest runoff samples. Maximum levels in runoff
water ranged from 1.00 µg/L (pre-emergence runoff) to 8.7 µg/L in harvest season runoff samples.
Glyphosate levels in surface water are summarized in Section 5.5.2.
Aparicio et al. (2013) measured the environmental fate of glyphosate and AMPA in surface water of
agriculture basins in Argentina. Forty-two streams were sampled in April, August and September of 2012.
Between the collection months, glyphosate was measured in 4% to 35% of samples with levels ranging
between trace to 7.6 µg l-1. AMPA was detected in up to 33% of samples collected and concentration
levels were measured between non-detect to 2.3 µg l-1. There was a decrease in the number of samples
detecting glyphosate or AMPA overtime, and this may be due to the dilution effect caused by rainfall,
which was measured as 65.7 mm (April) and 253.5 mm (August) (Aparcio et al. 2013).
5.3.3 Soil
There is no information on releases of glyphosate to soil from manufacturing and processing facilities
because these releases are not required to be reported (EPA 2005b).
Glyphosate applied directly to vegetation may migrate to the soil from foliar washoff or translocation
from the plants to the root zone. As discussed in Section 5.2.3, glyphosate agricultural uses in the United
States increased from about 20 million pounds in 1992 to about 300 million pounds by 2014 (USGS
2017). Battaglin et al. (2014) estimated that nonagricultural uses of glyphosate were about 9,300 metric
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tons (20.5 million pounds) in the United States in 2007 and Benbrook (2016) estimated that about
26.5 million pounds were used for nonagricultural purposes in 2014.
A 2008 survey of pesticide application in Ontario, Canada, conducted by the Ministry of Agriculture,
Food, and Rural Affairs reported that glyphosate use increased from an estimated 1,170,762 kg active
ingredient in 2003 up to an estimated 2,062,648 kg active ingredient in 2008 (OMAFRA 2008). A total
of 527,952 kg of glyphosate were used on field crops, 6,700 kg were used on fruit, 6,110 kg were used on
vegetables, and 6,635 kg of glyphosate were used on nursery crops, sod, and ginseng; greenhouse crops
were not included. Specific 2008 glyphosate applications for weed control by crop use amounted to
527,952 kg in production of field corn, 1,253,773 kg for soybean production, 11,087 kg for canola,
155,428 kg for wheat, 9,206 kg for oats, 6,588 kg for barley, 6,167 kg for mixed grains, 3,185 kg for rye,
18,054 kg for white beans, 18,661 kg for dry beans, 27,011 kg for hay, 2,717 kg for pasture, 1,386 kg for
sugar beets, and 1,991 kg for other field crops (OMAFRA 2008).
The environmental fate of glyphosate, which includes the transport, partitioning, and transformation of
this substance, is controlled by various physicochemical properties, degradation, and other loss processes.
Glyphosate is a non-volatile, highly polar, non-residual herbicide that has low potential for environmental
persistence and is unlikely to bioaccumulate; the chemical is either degraded or inactivated by adsorption
to soil (Smith and Oehme 1992). Microbial degradation in soils and water is an important fate process;
reported half-lives range from 2 to 215 days in soils and from 1.5 to 130 days in waters (Battaglin et al.
2014; IPCS 1994; PAN 2009; Rueppel et al. 1977). The wide range of half-lives is a result of
environmental conditions such as soil characteristics, pH, and endogenous microbial populations, which
are factors that influence the rate of degradation. Glyphosate is not expected to be susceptible to
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hydrolysis; photodegradation has not been confirmed as an important fate process in any environmental
media (Smith and Oehme 1992).
Glyphosate is not expected to change ionic form at pH levels of 5–8 and is expected to exist in its anionic
form under most environmental conditions.
Air. Glyphosate has a low vapor pressure and is expected to exist in the particulate phase in the ambient
atmosphere. There is potential for spray drift after application of herbicides, the extent of which is
dependent on the mode of application. Aerial applications may result in considerable transport depending
on climate conditions (Silva et al. 2018; IPCS 1994; Yates et al. 1978). Drift analysis has shown that 10–
37% of applied herbicide can drift to non-target plants. Seedling and plant fatalities were found 20–100
m downwind after application, and residues have been detected at 400 and 800 m downwind following
ground and aerial applications, respectively (PAN 2009). Wind erosion is one pathway in which
glyphosate and its primary metabolite, AMPA, are transported into the atmosphere; Silva et al. (2018)
estimated wind only can contribute between 1941 to 30,000 mg/ ha-1 year-1 in offsite transport in soils
with low to medium and high glyphosate content, respectively (Silva et al. 2018). Furthermore, Bento et
al. (2017), reported that glyphosate and AMPA content were highest in the smallest particle sample size
(8 µm) tested across three soil types (clay, organic matter, and silt). Glyphosate concentration ranged
between 5.5 to 15 µg/g and AMPA content ranged between 0.07 to 0.7 µg/g when particle sizes (8 µm to
715 µm) were analyzed. Because particles <20 µm can be transported in long-term suspension, it’s
possible that combined with wind speeds, glyphosate particles have the potential to travel long distances
and be transported into non-agricultural areas, particularly in conditions where topsoil is sufficiently dry
(Bento et al. 2017).
Particulate-phase glyphosate can be removed from the atmosphere by wet or dry deposition. Wet
deposition of glyphosate and its major degradation product, AMPA, from the atmosphere ranged from 3.9
to 16 µg/m2 and from 1.7 to 5.2 µg/m2, respectively, as reported in a study conducted in Pace,
Mississippi, and Blairsburg, Iowa in 2007 and 2008 (Chang et al. 2011). In a study conducted in 2001,
the total annual deposition for glyphosate was reported as 49,000 ng/m2 and the maximum concentration
detected was 6,200 ng/L. Glyphosate was detected in about 10% of the collected samples. The total
annual deposition for AMPA was reported as 12,757 ng/m2 and the maximum concentration detected was
1,200 ng/L. The majority of glyphosate detections occurred during the spraying season. Deposition rates
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and concentrations of glyphosate were higher at the urban sites; this was attributed to its non-agricultural
uses. The concentration of glyphosate and several other herbicides/pesticides were monitored in
rainwater in Belgium from 1997 to 2001, and glyphosate was found to have an average annual
concentration of 78 ng/L. The concentration increased dramatically during spraying season, reaching a
maximum of 6,200 ng/L (Quaghebeur et al. 2004).
Water. Depending on its application, glyphosate may enter aquatic environments through direct
application, or as a result of overspray in areas near aquatic environments .Water erosion is another route
in which glyphosate and AMPA are transported into surface water bodies; Silva et al. (2018) estimated
water erosion can contribute between 9753 to 47,557 mg/ ha-1 year-1 in soils with low to medium and high
glyphosate content, respectively (Silva et al. 2018). There is evidence of limited run-off and leaching
with sandy soils and heavy rainfall (Borggaard and Gimsing 2008). Partitioning into aqueous
environments is attenuated by adsorption to soils and sediments.
Sediment and Soil. Glyphosate will have strong adsorption to most soils due to its ionic nature and is
expected to bind to positively charged metal surfaces present in clay and soils. Adsorption occurs
through hydrogen bonding ion exchange or complexes of the phosphonate anion as well as the
ammonium cation with minerals present in soils (Miles and Moye 1988). In an unpublished report by
Monsanto in 1978, <0.1–6.6% of applied activity was recovered in the solution that washed off of the soil
columns under leaching conditions simulating a heavy rainfall (IPCS 1994). The potential for run-off and
leaching ability of glyphosate was examined by Rueppel et al. (1977) in three soils. Using inclined soil
beds and artificial rainfall scenarios, a maximum runoff off <2x10-4 kg/ha was reported. Using thin layer
chromatography and beta camera analysis, 97–100% adsorption to all three soils indicated that there is
minimal possibility for leaching into groundwater. Although glyphosate is expected to adsorb strongly to
soil particles and clay minerals, desorption may occur under certain conditions. It has been demonstrated
that sorption decreases with increasing soil pH, increasing concentrations of inorganic soil phosphate, and
decreasing mineral concentrations (Glass 1987; Gerritse et al. 1996; Piccolo et al. 1994; Plimmer et al.
2004; Smith and Oehme 1992; Sprankle 1975). However, because of the strong sorption to most soils,
mobility and the potential for migration into groundwater are low. It is known that glyphosate and
AMPA strongly adsorb and accumulate in the top of soils (Silva et al. 2018). The major degradation
product, AMPA (CASRN 1066-51-9), also binds to soils and may be more mobile than glyphosate (Duke
and Powles 2008; IPCS 1994). Leaching of glyphosate may be possible under certain environmental
conditions. In a study examining the environmental fate and leaching risk of aged glyphosate and its
metabolite, AMPA, large amounts of glyphosate and AMPA were extracted from soil after treating it with
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phosphate solution (to simulate rainwater in the presence of fertilizer) compared to pure water (to
stimulate rainwater in non-fertilized soil). The presence of phosphate based fertilizer in soil appears to
enhance the probability that glyphosate and its metabolite residue will leach from the soil matrix
(Simonsen et al. 2008). While glyphosate and AMPA have been reported to reach shallow groundwater
and then transfer to surface water (Grandcoin et al. 2017), the chemical is not expected to leach into
groundwater as it is mostly concentrated in the topsoil layers; Glyphosate and AMPA are infrequently
detected in deep groundwater systems, and when found, concentrations are generally at low levels (Silva
et al. 2018).
Other Media. Glyphosate is not generally taken up from the soil by a plant’s root system since it
typically forms bound residues with organic matter in most soils. Absorption of glyphosate via the roots
has been discussed in a review by Saunders and Pezeshki (2015); however, many of the studies cited were
conducted under hydroponic conditions, which are not likely to be typical of field environments.
However, some uptake has been demonstrated to occur under field conditions with low organic-
containing soils and in laboratory growing conditions. The EPA Registration Eligibility Decision (RED)
document for glyphosate showed that lettuce, carrots, and barley contained glyphosate and AMPA
residues after a sandy loam containing 0.3–0.5% organic matter was treated with 3.71 pounds of
glyphosate per acre, but accumulation decreased as the length of rotation increased. For example,
glyphosate residues were 0.097 ppm in lettuce planted 30 days post-treatment, but only 0.037 ppm in
lettuce planted 119 days post-treatment (EPA 1993). After surface application of glyphosate, it may
move from the point of application, typically the leaves, to other parts of the plant. In a plant uptake
study where glyphosate was aged for 6.5 months in soil before either rape or barley seeds were planted,
radioactivity demonstrated translocation of glyphosate into the parts of the plant above the soil after a
growth period of 41 days. The measured uptake for rape and barely were equivalent to 14.0 and 11.5
ng/glyphosate/g plant fresh weight, respectively (Simonsen et al. 2008). Glyphosate can be absorbed into
the plant or vegetable through its outer wall or skin and can move throughout the stem and leaves of the
entire plant. Metabolism of glyphosate within the plant occurs slowly (Doublet et al. 2009; Smith and
Oehme 1992; WHO 2005). Glyphosate is mobile inside the plant and may be transported within the
phloem system into other tissues before the plant is killed (Duke and Powles 2008; Pankey 2000;
Plimmer et al. 2004). Boerboom and Wyse (1988) investigated absorption and translocation of
glyphosate using Canada thistle seeds with various concentrations of a formulation of glyphosate (356
g/L) and the surfactant POEA (178 g/L). Translocation from the treated leaf to the root was clearly
observed. Translocation generally decreased as the concentration of glyphosate increased. Application of
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the smaller droplets resulted in greater translocation to the roots compared to application of larger
droplets.
Glyphosate is readily and completely degraded in the environment mainly by microbial processes.
Microorganisms that degrade glyphosate into its metabolite include Pseudomonas sp., Arthrobacter
atrocyaneus and Flavobacterium sp. (Singh and Singh 2016). Modes of degradation involving glyphosate
oxidoreductase (GOX) and C-Plyase enzymatic pathways have been suggested. AMPA has been
identified as the major metabolite in both soils and water. Sarcosine is an additional degradation product
produced by the C-Plyase enzymatic pathway (Singh and Singh 2016). However, sarcosine has mostly
been found in pure culture experiments, likely due to its fast degradation compared to AMPA (Borggaard
and Gimsing 2008). Glyoxylic acid (CASRN 298-12-4) is an additional degradation product by the GOX
enzymatic pathway. Both pathways result in complete mineralization to inorganic phosphate, carbon
dioxide, ammonium, and water (Balthazor and Hallas 1986; Kishore and Jacob 1987; Shinabarger and
Braymer 1986). AMPA is more persistent than glyphosate and has reported soil half-lives ranging from
32 to 240 days depending on edaphic and environmental conditions such as temperature and soil moisture
(Simonsen et al. 2008; Battaglin 2014; Silva et al. 2018). At colder and drier conditions, degradation of
AMPA is slower (Silva et al. 2018). Aquatic half-lives are similar to glyphosate (Battaglin 2014). Figure
5-2 illustrates the degradation of glyphosate under aerobic conditions.
Figure 5-2. Degradation of Glyphosate Under Aerobic Conditions
The high water solubility, low log Kow, and ionic nature of glyphosate suggest that this compound would
not be expected to bioaccumulate in aquatic organisms (IPCS 1994; WHO 2005). Jackson et al. (2009)
measured whole-body bioconcentration factor (BCF) values for glyphosate in bluegill fish (Lepomis
macrochirus) using EPA guideline method OPPTS 850.1730 for an exposure period of 28 days. A BCF
value of 0.52 (log BCF -0.284) was reported, suggesting that bioconcentration was low. Accumulated
residues of glyphosate in fish, crustaceans, and mollusks exposed to water containing glyphosate declined
approximately 50–90% over 14–28 days after removal from the glyphosate water into glyphosate-free
water (WHO 2005). Bioaccumulation of glyphosate in blackworms (Lumbriculus variegatus), following
soil application of glyphosate and a commercial formulation, was investigated (Contardo-Jara et al. 2009).
BCF values after 4 days of exposure to concentrations of 0.05–5 mg/L of both 98% pure glyphosate and
the formulation Roundup Ultra® were measured at 20°C (Contardo-Jara et al. 2009). BCF values based
on the fresh weight of the worms ranged from 1.2 to 5.9; the BCF values for pure glyphosate at 0.05, 0.5,
and 5.0 mg/L were approximately 2.9, 1.1, and 2.8, respectively and BCF values for Roundup Ultra® at
0.05, 0.5, and 5.0 mg/L were approximately 5.9, 3.8, and 2.7, respectively. The greater uptake of
glyphosate from the Roundup Ultra® sample was attributed to the surfactant in the formulation, POEA.
The mechanism of action for glyphosate’s herbicidal properties involves the inhibition of enzymes in the
shikimate pathway. Specifically, the enzyme enolpyruvylshikimate-3-phosphate synthase is inhibited,
creating a deficiency of enolpyruvylshikimate-3-phosphate and an abundance of shikimate. It has been
suggested that the actual death of the plant is due to the disruption of plant processes regulated by the
shikimate pathway essential to plant health and growth such as the primary biosynthesis of aromatic
amino acids like phenylalanine, tryptophan, and tyrosine, as well as lignin and chlorophyll, and secondary
processes such as flavonoid synthesis. These primary processes are exclusive to plants and some
microorganisms and do not occur in any animals; therefore, the inhibition of enzyme production induced
by glyphosate only affects species in the plant kingdom. It has also been suggested that the increased
carbon flow to the shikimate pathway decreases carbon available for other essential photosynthetic
processes (Muller and Applebyke 2010; Pankey 2000; Plimmer et al. 2004; Servaites et al. 1987).
Air. Glyphosate has low vapor pressure and is considered stable in ambient air. Experimental and
monitoring studies have confirmed wind-driven transportation of both glyphosate and AMPA including in
areas that never had glyphosate application (Silva et al. 2018; Aparicio et al. 2018).
Water. Glyphosate is polar, has high water solubility and is expected to exist as an anion at neutral pH
(IPCS 1994; O’Neil et al. 2013; Singh and Singh 2016). Based on experimental adsorption coefficients
ranging from 8 to 377 dm3/kg for various soil and clay substrates, glyphosate is expected to adsorb to
suspended solids and sediments in water. Precipitation from water has been suggested due to water-
insoluble metal complexes with iron(III), copper(II), calcium, and magnesium that have been found;
coordination occurs through the amine nitrogen, the carboxylic oxygen, and the phosphate oxygen
(Subramaniam and Hoggard 1988). Photodegradation in water is not expected to be an important fate
process for glyphosate under environmentally relevant conditions. Experimental half-lives of <28 days
upon exposure to natural light have been reported (IPCS 1994; Rueppel et al. 1977). No detectable
photodegradation was observed in a study using sterile water and exposure to ultraviolet (UV) light or
natural sunlight (Smith and Oehme 1992). Lund-Hoie and Friestad (1986) exposed RoundUp® to UV
light at 254 nm at 20°C in the laboratory and exposed 1% RoundUp® solutions in deionized water,
polluted water, and water with suspended sediments to natural sunlight (measured λ=295–385 nm)
outside at temperatures ranging from 20 to -5°C. Results indicated that photodegradation occurred faster
in pure water as opposed to polluted water or water with sediments in which adsorption accounted for the
majority of dissipated glyphosate. A photolytic half-life of 3–4 weeks was observed for glyphosate, at an
initial concentration of 2,000 ppm in the deionized water exposed to UV light. A photolytic half-life of 5
weeks at 100 ppm was observed for glyphosate in deionized water, exposed to natural sunlight. The rate
of hydrolysis is considered very slow. In a study at 35°C, glyphosate did not undergo hydrolysis in
buffered solutions with a pH of 5, 7, or 9. Laboratory studies have reported 50% degradation in ≤14 days
in water and sediment under aerobic conditions and 14–22 days under anaerobic conditions for glyphosate
(IPCS 1994). In an aqueous hydrolysis study at 25°C in buffered solutions of pH 5, 7, and 9, glyphosate
was considered hydrolytically stable, with extrapolated half-lives beyond 3 years (EPA Undated).
Rapid dissipation of glyphosate in small forest ponds was observed as a result of sediment sorption and
microbial degradation (Goldsborough and Beck 1989). Dissipation in three ponds, pH 5.0–7.7, resulted
GLYPHOSATE 177
in half-lives of 1.5–3.5 days. After 38 days, glyphosate was not detected in any of the samples. AMPA
concentrations were consistently low throughout the study.
Microbial degradation of glyphosate in water sediments has been investigated. AMPA has been
identified as the major metabolite in water. Rueppel at al. (1977) performed non-sterile and sterile
soil/water shake flask experiments to examine the degradation of glyphosate under aerobic and anaerobic
conditions. The 14C-labeled glyphosate samples used were between 94.8 and 98.1% pure. Ray silt loam,
Norfolk sandy loam, and Drummer silty clay loam soil samples were used. In the sterile soil test, 1.0%
degradation was achieved after 7 days; the report suggests that abiotic chemical degradation is not a likely
fate process for glyphosate. In non-sterile aerobic and anaerobic tests using Ray silt loam and 14C-labeled
glyphosate, 46.8–55.3 and 33.5–51.4% TCO2 (theoretical CO2 evolution), respectively, was achieved after
28 days. In the non-sterile aerobic tests using fresh and bin-stored Drummer loams, just over 40% and just
under 20% TCO2, respectively, was achieved after 28 days. In the fresh Drummer loam and Ray loam
samples, no lag phases were observed, and the bulk of the degradation occurred by day 7, after which
time, the rate of degradation declined. The slowing of degradation was attributed to adsorption to soil. In
Ray silt loam and Drummer silty clay loam, degradation of glyphosate reached 90% after 14 and 80 days,
respectively, and half-lives were reported as 3 and 25–27 days, respectively. The results were similar at
different concentrations of glyphosate. In the non-sterile aerobic test in Norfolk sandy loam, carbon-
labeled glyphosate achieved <10% mineralization after 28 days, measured by applied 14C as CO2
evolution, and 43% dissipation occurred after 112 days. A half-life of 130 days was reported for Norfolk
soil. The principle degradation product identified, AMPA, was confirmed in soil samples by nuclear
magnetic resonance (NMR) imaging, mass spectral analysis, ion-exchange chromatography, and thin-
layer chromatography. Minor degradation products identified included N-methylaminomethylphosphonic
acid, glycine, N,N-dimethylaminomethylphosphonic acid, and hydroxymethylphosphonic acid, all of
which were typically present at <1% (Rueppel et al. 1977). The metabolite, AMPA, achieved 16.1 and
34.8% degradation after 63 days in Drummer and Ray loams, respectively, measured by applied 14C as
CO2 evolution.
Abiotic degradation was examined by Ascolani Yael et al. (2014) in aqueous solution in the presence of
copper salts; results indicated that glyphosate interactions with metal ions in soils may catalyze
degradation to AMPA. Further investigation was proposed.
Sediment and Soil. Glyphosate is readily degraded in the terrestrial environment by a variety of
microorganisms. Bacteria, actinomycetes, fungi, and other soil microbes have the ability to degrade
GLYPHOSATE 178
glyphosate. AMPA has been identified as the major metabolite in soil. Glyphosate may also be degraded
in soil to sarcosine and inorganic phosphate. Photodegradation is not expected to be an important fate
process in soil.
After application of Roundup® at about 2.0 kg/ha (acid equivalent of isopropylamine salt of glyphosate)
to Carnation Creek watershed (10 km2 study area), 50% of the glyphosate residues in soil dissipated after
45–60 days and 82–94% dissipated after 360 days (Feng et al. 1990a).
It has been demonstrated that inorganic phosphate present in soils may inhibit some microbial degradation
of glyphosate (Kishore and Jacob 1987). Strains capable of using glyphosate as a sole carbon, nitrogen,
or phosphorus source, thereby degrading glyphosate, include Flavobacterium sp. (Balthazor and Hallas
1986), which is known to degrade glyphosate in the presence of phosphate, Pseudomonas sp. PG2982
(Kishore and Jacob 1987; Shinabarger and Braymer 1986), Arthrobacter atrocyaneus (Pipke and
Amrhein 1988), and Rhizobium spp. (Liu et al. 1991). Biodegradation may involve co‐metabolism with
other energy sources as well (Sprankle et al. 1975). Degradation products include AMPA and glyoxylic
acid, which are subsequently degraded to inorganic phosphate, carbon dioxide, and ammonium. In
addition, some bacterial degradation results in the production of sarcosine and inorganic phosphate
(Borggaard and Gimsing 2008; Kishore and Jacob 1987; Liu et al 1991; Pipke and Amrhein 1988;
Shinabarger and Braymer 1986).
Microbial degradation of bound and unbound glyphosate in several soils resulted in 17.4–45% ultimate
degradation after 28 days; the highest degradation rate was observed in Conover sandy clay loam soil
(Sprankle et al. 1975). The majority of the degradation was attributed to co-metabolic processes of soil
microbes, with possible chemical degradation occurring.
In a biodegradation experiment with activated sludge, the bacterial strain, Flavobacterium sp., was
identified as the microorganism metabolizing glyphosate to AMPA. This degradation was followed by
complete mineralization of AMPA, using the enzyme phosphonatase, to carbon dioxide (CO2), phosphate
(PO43-), ammonium (NH4+), and water (H2O) (Balthazor and Hallas 1986).
A variety of microorganisms are capable of degrading glyphosate. In one degradation pathway, the initial
step involves cleavage of the carbon-phosphate bond to produce sarcosine and inorganic phosphate. This
is followed by conversion of sarcosine to glycine and formaldehyde. Pseudomonas sp. PG2982 uses the
enzyme, C-P lyase, to cleave the carbon-phosphate bond in glyphosate, producing sarcosine. This is
GLYPHOSATE 179
followed by the cleavage of sarcosine into glycine and formaldehyde (Kishore and Jacob 1987;
Shinabarger and Braymer 1986). Glycine and formaldehyde are metabolized in other biosynthesis
processes, such as the oxidation of formaldehyde to carbon dioxide. Multiple strains in the bacterial
family Rhizobiaceae have the ability to metabolize glyphosate. Liu et al. (1991) found that rhizobia
bacterial cells took up close to 85% of available glyphosate within 30 minutes, after which time, the
percentage began to decrease. Thin layer chromatography confirmed the presence of sarcosine and
glycine as degradation products.
Doublet et al. (2009) studied the degradation of plant absorbed glyphosate in soils. Plants containing
residues of glyphosate can enter the soils during crop cycling or harvesting. Degradation of glyphosate
was different depending on the plant tissue in which it was absorbed. Mineralization rate constants
(k (day-1)) ranged from 0.031 to 0.097 in the apex of oilseed rape and in the lamina of maize, respectively.
It was noted that absorption of glyphosate in plants delayed degradation in soil.
Glyphosate is expected to adsorb strongly to soil particles and clay minerals; however, the amount of
glyphosate sorbed decreases with increasing soil pH. Adsorption and desorption of glyphosate were
examined using HPLC (Gerritse et al. 1996; Glass 1987; Piccolo et al. 1994; Sprankle et al. 1975).
Adsorption to agricultural soils and clay minerals and the effects of pH and cation saturation were
examined by Glass (1987). The Koc values were 4,900 for clay loam with pH 7.5 and organic content
(OC) of 1.56%; 3,400 for silt loam with pH 5.8 and OC of 1.64%; and 2,600 for sandy loam with pH 5.6
and OC of 1.24%. The adsorption and desorption of glyphosate and the effects of soil characteristics in
four various soil types were assessed (Piccolo et al. 1994). Some characteristics for the four soils follow:
Sample A, pH 8.0 and 0.00 OC % (64.1% silt); sample B, pH 5.8 and 3.73 OC% (46.3% sand); sample C,
pH 4.6 and 9.23 OC % (81.5% sand); and sample D, pH 8.3 and 0.45 OC % (82.4% silt). The greatest
adsorption occurred in the soil with the highest concentrations of iron (4.74%) and aluminum (1.57)
oxides (sample B); the greatest desorption occurred in the soil with lowest concentration of iron (0.18%)
and aluminum (0.16%) oxides (sample A). The percent desorptions of glyphosate from the four soils
were 81% in sample A, 15% in sample B, 72% in sample C, and 35% in sample D. A ligand exchange
mechanism is hypothesized for the adsorption of glyphosate involving either the phosphonic component
or the carboxylic component of this substance and adsorption to iron and aluminum sites (Benetoli et al.
2010; Piccolo et al. 1994). The adsorption and desorption of both glyphosate and its metabolite, AMPA,
were examined by Gerritse et al. (1996) using five soil types. Koc values calculated for soil organic
carbon ranged from 8.5 to 5x106 after 1 day and from 45 to >5x106 after 1 week. The strongest
adsorption occurred in the soil with the highest iron and aluminum content. The weakest adsorption
GLYPHOSATE 180
occurred in the soil with the highest organic content. These results indicate that glyphosate has a notable
affinity towards some soils, particularly with lower pH values and greater mineral content, and desorption
occurs under certain environmental conditions especially as pH values increase and mineral
concentrations decrease. The EPA CompTox Chemicals Dashboard provided a predicted Koc range of
0.00169–2,080 L/kg, which again indicates a range of mobility in soil likely determined by affinity
towards these soil properties.
During a monitoring study with mixtures of Roundup® plus an additional herbicide, soil adsorption and
desorption studies were performed on soils from Baton Rouge, Bridge City, and Hammond Louisiana
(LaDOTD 1995). The Hammond soil with a pH <8 adsorbed >90% of the applied glyphosate.
Adsorption values (Kf) were 8.7, 0.1, and 0.34 for Baton Rouge, Bridge City, and Hammond soils,
respectively. Desorption values (Kd) were 355, 0.04, and 0.005 µg/g for Baton Rouge, Bridge City, and
Hammond soils, respectively.
Greater than 90% of the glyphosate residues detected in forest soil samples (pH 4.20–5.28), where
herbicides containing glyphosate had been sprayed, were found in the upper layers (depth of 0–15 cm) of
the soils in both seasonally flooded and well-drained soils, indicating minimal leaching of glyphosate
(Feng et al. 1990b).
Glyphosate dissipates from soil under certain environmental conditions. Half-life values between 2 and
215 days have been reported (Battaglin et al. 2014). In field experiments, dissipation from the soil due to
run‐off has been demonstrated (IPCS 1994). Landry et al. (2005) examined the leaching potential and
mineralization of glyphosate in vineyard soils by monitoring outdoor soil columns from May 2001 to
May 2002. Bare and grass-covered soils with pH values ranging from 8.0 to 8.4 were studied. Sand, silt,
and clay contents were 23.8–34.4, 36.5–39.6, and 29.1–36.9%, respectively, of the bare soils and 26.2–
35.6, 34.2–41.3, and 29.6–32.5%, respectively, of grass-covered soils. An aqueous solution of herbicide
containing 340 mg/L glyphosate was applied to both soil column surfaces. Effluents from the bare and
grass-covered soils were collected weekly and after heavy precipitation to evaluate leaching of glyphosate
and AMPA. Glyphosate was detected in 37% of the bare soil leachates and 27% of the grass-covered soil
leachates. The highest concentrations measured from the bare soil leachate and grass-covered leachate
were 17 and 2.7 µg/L, respectively. AMPA was detected in 90% (maximum concentration 9.4 µg/L) of
the bare soil leachates and 41% (maximum concentration 3.5 µg/L) of the grass-covered soil leachates.
Mineralization analysis was performed at 20°C for 42 days in both soils. In the grass-covered soil and
bare soil, 14C-labeled glyphosate achieved 46.5 and 43.5% CO2 evolution after 42 days, respectively.
GLYPHOSATE 181
Rapid degradation was observed with no lag phase; the highest rate of degradation occurred within the
first 2 days. It was suggested that the initial rapid degradation was based on the degradation of free
glyphosate and slowing rates of degradation were attributed to the degradation of adsorbed glyphosate.
Other Media. After application of herbicides, 30–97% of the applied glyphosate may be taken up by
the plant by absorption from the treated leaves. Glyphosate-based formulations containing surfactants
(and adjuvants) have a higher rate of absorption compared to glyphosate water solutions (Doublet et al.
2009). Surfactants in herbicide formulations aid in the adsorption and absorption of the active ingredient.
Glyphosate is absorbed by plant foliage and transported or moved through the plant via phloem vessels;
translocation patterns depend on the specific species of plant. Glyphosate enters these vessels slowly, but
once inside, it becomes ‘trapped’ because of the pH within the vessels, which causes ionization (Gomes et
al. 2014; IPCS 1994). Glyphosate may be degraded or metabolized in plants, AMPA is a notable
degradation product (Duke 2011). An examination of the metabolism of glyphosate in soybean and
canola suggest that some plants use a GOX enzyme for the conversion of glyphosate to AMPA.
Degradation of glyphosate in glyphosate-resistant crops may give a better picture of the metabolic
processes without interferences found in conventional crops. In transgenic plants modified to be
glyphosate tolerant, glyphosate is converted to N-acetylglyphosate, which lacks herbicidal properties
(Pioneer 2006). This chemical may be further metabolized to N-acetyl-AMPA (PAN 2009). Glyphosate
and AMPA accumulate less in glyphosate-resistant crops than in conventional crops. Lower glyphosate
and AMPA levels in glyphosate-resistant canola compared to conventional crops suggested that
metabolism is more rapid in glyphosate-resistant canola (Duke 2011).
Reliable evaluation of the potential for human exposure to glyphosate depends, in part, on the reliability
of supporting analytical data from environmental samples and biological specimens. Concentrations of
glyphosate in unpolluted atmospheres and in pristine surface waters are often so low as to be near the
limits of current analytical methods. In reviewing data on glyphosate levels monitored or estimated in the
environment, it should also be noted that the amount of chemical identified analytically is not necessarily
equivalent to the amount that is bioavailable.
Table 5-4 shows the lowest limits of detection (LODs) that are achieved by analytical analysis in
environmental media. An overview summary of the range of concentrations detected in environmental
media is presented in Table 5-5.
GLYPHOSATE 182
aDetection limits based on using appropriate preparation and analytics. These limits may not be possible in all
situations.
A study by the USGS evaluated 3,732 environmental samples across 38 states and the District of
Columbia from several studies examining glyphosate in the environment; the samples were collected
between 2001 and 2010 from 1,341 different sites, including groundwater; lakes, ponds, and wetlands;
soil water; streams; large rivers; precipitation; ditches and drains; soil and sediment; and waste water
treatment plant outfall (Battaglin et al. 2014). Glyphosate was detected in 39.4% of all the samples, with
a median value of <0.02 µg/L and a maximum value of 476 µg/L. Its degradation product, AMPA, was
detected in 55% of all the samples, with a median value of 0.04 µg/L and a maximum value of 397 µg/L.
GLYPHOSATE 183
Groundwater (n=1,171) had the smallest percentage of detections, with 5.8% for glyphosate and 14.3%
for AMPA. Glyphosate was detected in 53% of the 1,508 stream samples and AMPA was detected in
72%. Glyphosate was detected in 34% and AMPA was detected in 30% of the 104 small body water
samples such as lakes and ponds. Out of 11 wastewater treatment plant (WWTP) samples, glyphosate
and AMPA were detected in 9.1 and 82%, respectively. Out of 85 precipitation samples, glyphosate was
detected in 71% and AMPA was detected in 72%. Glyphosate was detected in 71% of the 374 ditch and
drain samples, with a median value of 0.02 µg/L and a maximum value of 427 µg/L. Glyphosate was
only detected without its degradation product, AMPA, in 2.3% of all of the samples; AMPA was detected
without glyphosate in 17.9% of the samples. In 42.7% of all of the samples, neither analyte was detected.
Several sites with multiple samples during the years 2001–2005 and 2006–2010 indicated that the
detection frequency and median concentration of both glyphosate and AMPA had increased in the
environment (Battaglin et al. 2014). The highest level of glyphosate was detected in soils and sediments.
Out of 45 samples, glyphosate was detected in 91%, with a median value of 9.6 µg/kg and a maximum
value of 476 µg/kg. AMPA was detected in 93.3% of 45 samples, with a median value of 18 µg/kg and a
maximum value of 341 µg/kg.
5.5.1 Air
Ambient air monitoring data for glyphosate are compiled in Table 5-6.
Median concentration
Location Date (range) in ng/m3 Notes Reference
Agricultural 2007 Glyphosate: 0.48 (<0.01–9.1) Glyphosate and AMPA detected in Chang et al.
ambient air; AMPA: 0.06 (<0.01–0.49) 19/22 air samples 2011
Mississippi
2008 Glyphosate: 0.24 (<0.01–1.5) Glyphosate and AMPA detected in
AMPA: 0.02 (<0.01–0.09) 27/27 and 19/27 air samples,
respectively
Agricultural 2007 Glyphosate: 0.08 (<0.01–5.4) Glyphosate and AMPA detected in Chang et al.
ambient air; AMPA: 0.02 (<0.01–0.97) 11/18 and 10/18 air samples 2011
Iowa
2008 Glyphosate: 0.22 (<0.01–7.7) Glyphosate and AMPA detected in
AMPA: 0.04 (<0.01–0.38) 13/18 and 11/18 air samples
Agricultural June <0.1–138.6 µg/m Breathing zone air (110 samples); LaDOTD
breathing 19, sampled in areas where mixtures of 1995
zones; 1990– commercial herbicides were
Baton October applied using spray equipment with
Rouge, 9, 1990 operating capabilities of
Bridge City, 0.37 L/minute
GLYPHOSATE 184
Median concentration
Location Date (range) in ng/m3 Notes Reference
Hammond,
Louisiana;
5.5.2 Water
A comprehensive study conducted by the USGS from 2001 to 2006 examined glyphosate and its
degradation product, AMPA, in 2,135 groundwater and surface water samples, 14 rainfall samples, and
193 soil samples in major river basins in the United States (USGS 2007). Results indicated that AMPA
was detected more frequently and at similar concentrations than parent glyphosate in many samples. The
results are summarized in Table 5-7.
Glyphosate AMPA
Maximum Minimum Maximum Minimum
N Detections (µg/L) (µg/L) Detections (µg/L) (µg/L)
Groundwater
873 68 4.7 0.02 133 2.6 0.02
Surface water
1,262 489 427 0.02 725 41 0.02
Rainfall
14 12 1.1 0.3 12 0.47 0.02
Additional water monitoring data for glyphosate are compiled in Tables Table 5-8 and Table 5-9.
Sediment and soil monitoring data for glyphosate are compiled in Table 5-10.
In 2006, 20 prepared food samples were examined for glyphosate residues using electrospray ionization–
liquid chromatography tandem mass spectrometry with limit of quantitation of 0.01 mg/kg and an LOD of
0.005 mg/kg (McQueen et al. 2012). Composite food samples assessed had a mean concentration of
0.08 mg/kg.
Four weeks post application of glyphosate at 4.5 kg/ha to separate pots planted with conventional corn,
cotton, soybeans, and wheat, concentrations of glyphosate were 0.21, 0.26, 0.20, and 0.20 mg/kg,
respectively. Six weeks after application, concentrations in corn, cotton, soybeans, and wheat were 0.14,
0.21, 0.29, and 0.18 mg/kg, respectively, and 8 weeks after application, concentrations in corn, cotton,
soybeans, and wheat were 0.079, 0.42, 0.076, and 0.35 mg/kg, respectively (FAO 2005). Four-week
concentrations of glyphosate in control crops of corn, cotton, soybeans, and wheat were 0.068, 0.04,
0.029, and 0.008 mg/kg, respectively. Six-week concentrations in control crops of corn, cotton, soybeans,
and wheat were 0.089, 0.020, 0.11, and 0.015 mg/kg, respectively, and 8-week concentrations in control
crops of corn, cotton, soybeans, and wheat were 0.022, 0.27, 0.045, and 0.061 mg/kg, respectively (FAO
2005).
GLYPHOSATE 186
2008 Glyphosate: Median: 0.15 (<0.1–1.6) Glyphosate and AMPA detected in 13/11 and
AMPA: Median: <0.1 (<0. 1–0.48) 14/19 samples, respectively
Rainwater 2007 Glyphosate: Median: 0.2 (<0.1–2.5) Glyphosate and AMPA detected in 10/14 and Chang et al.
Iowa AMPA: Median: <0.1 (<0. 1–0.2) 5/14 samples, respectively 2011
2008 Glyphosate: Median: 0.1 (<0.1–1.8) Glyphosate and AMPA detected in 15/24 and
AMPA: Median: <0.1 (<0. 1–0.24) 12/24 samples, respectively
Rainwater 2004 Glyphosate: Median: 0.14 (<0.1–1.1) Glyphosate and AMPA detected in 11/12 and Chang et al.
Indiana AMPA: Median: <0.1 (<0.1–47) 11/12 samples, respectively 2011
Rainwater 2001 Maximum during spraying season: Glyphosate detected in 10% of samples; AMPA detected Quaghebeur et
Flanders, Glyphosate: 6,200 ng/L in 13% of samples al. 2004
Belgium AMPA: 1,200 ng/L
Average annual concentrations:
Glyphosate: 78 ng/L
AMPA: 20 ng/L
Streams of 2012 Glyphosate: 0.5 µg/L – 7.6 µg/L Glyphosate detected in 35%, 10% and 4% samples Aparicio et al.
Southeast collected in April, August and September, respectively. 2013
Buenos Aires,
Argentina AMPA: non-detect to 2.3 µg/L AMPA detected in 33% and 7%, of samples in April and
August, respectively. AMPA was not detected in samples
collected in September.
Gualeguay or 2012 Glyphosate: 0.73 µg/L Glyphosate detected in 3/11 samples; AMPA detected in Primost et al.
Gualeguaychu 6/11 samples. 2017
River, AMPA: 0.53 µg/L
Argentina
AMPA = aminomethylphosphonic acid; EPA = U.S. Environmental Protection Agency; MDL = method detection limit; STORET = STOrage and RETrieval;
USGS = U.S. Geological Survey
GLYPHOSATE 189
Concentration
Location Date (µg/L) Notes Reference
Drainage 2001 through 0.02–4.7 Glyphosate and AMPA measured in 873 groundwater samples. Glyphosate USGS 2007
basins for 2006 detected in 68 groundwater samples, and AMPA detected in 133 groundwater
surface- samples.
water or
rainwater
sampling
sites from
multiple
USGS
studies in
Florida,
Georgia,
Illinois, Iowa,
Kansas,
Mississippi,
Nebraska,
South
Dakota,
Vermont, and
Washington
Groundwater September 9, 1.6 EPA STORET data: Routine monitoring sample from USGS Wyoming Water WQP 2017
Wyoming 2010 Science Center
Groundwater March 2, 2010 0.14 EPA STORET data: Routine monitoring sample from USGS Florida Water WQP 2017
Florida Science Center
Groundwater April, October, 0.03–2.2 EPA STORET data: Routine monitoring sample from USGS Louisiana Water WQP 2017
Louisiana and November Science Center; depths 43.5–82 feet
2011
Groundwater February and 0.01–0.06 EPA STORET data: Routine monitoring sample from USGS Alabama Water WQP 2017
Alabama April, 2012 Science Center; USGS Texas Water Science Center
Texas
Groundwater June and August 0.02–0.24 EPA STORET data: Routine monitoring sample from USGS Kansas Water WQP 2017
Kansas 2014, June 2015, Science Center
July 2016
GLYPHOSATE 190
Concentration
Location Date (µg/L) Notes Reference
Groundwater 2001–2010 Median: <0.02 Detected in 68 out of 1,171 samples Battaglin et al.
23 U.S. Maximum: 2.03 2014
states
Groundwater 2008 0.02 Detected in 1 out of 13 well; not detected in 14 wells sampled in 2005 USGS 2010
Washington,
DC
Well water October and Not detected EPA STORET data: Routine monitoring sample from Minnesota Department WQP 2017
Minnesota November 2014, of Agriculture Pesticide Monitoring Program; activity depth reported at 0 m
2015
Aquifer, January and Not detected Ground water collected from pump 40 to 60 meter deep aquifer Primost et al.
Mesopotamia March 2012 2017
Pampas,
Argentina
EPA = U.S. Environmental Protection Agency; STORET = STOrage and RETrieval; USGS = U.S. Geological Survey
GLYPHOSATE 191
AMPA = aminomethylphosphonic acid; EPA = U.S. Environmental Protection Agency; MDL = method detection limit; STORET = STOrage and RETrieval;
USGS = U.S Geological Survey
GLYPHOSATE 193
A Joint FAO/WHO Meeting on Pesticide Residues summarized glyphosate concentrations found in edible
foods following applications of glyphosate formulations representative of several authorized use patterns.
Glyphosate concentrations ranged from undetectable, ≤0.05 mg/kg, in several foods like bananas and
selected meats to 3.7 mg/kg in a variety of grains and grain-based products (FAO 2005; FAO and WHO
2016). Genetically modified, and conventional food samples were studied. Herbicidal application
techniques used on the food samples examined included pre-harvest application, directed ground spray,
pre-emergence, and recirculating spray application methods. Application rates ranged from 0.36 to 7.7
kg/ha. The highest concentration found in banana pulp was 0.16 mg/kg. All kiwifruit assessed in the
study had undetectable residues. Olives had residues ranging from undetectable to 12 mg/kg. Dry beans
had residues ranging from undetectable to 10 mg/kg. Dry peas had residues ranging from undetectable to
8.9 mg/kg. Lentils had residues ranging from undetectable to 17 mg/kg. Glyphosate-tolerant sugar beet
root had residues ranging from undetectable to 8.6 mg/kg. Conventional maize had residues ranging from
undetectable to 3 mg/kg. Glyphosate-tolerant maize had residues ranging from undetectable to 0.83
mg/kg. Oats had residues ranging from undetectable to 19 mg/kg. Rye grain had residues ranging from
0.1 to 4.6 mg/kg. Wheat grain had residues ranging from 0.09 to 6.4 mg/kg. Sugarcane had residues
ranging from undetectable to 15 mg/kg. Coffee and tea had levels ranging from undetectable to 9.6
mg/kg. Glyphosate residues in Kona Hawaiian coffee beans prior to roasting were 0.58 mg/kg, and the
roasted beans had residues of 0.06 mg/kg.
Glyphosate was not included in compounds tested for by the Food and Drug Administration’s (FDA)
Pesticide Residue Monitoring Program (PRMP), nor in the United States Department of Agriculture’s
Pesticide Data Program (PDP) (FDA 2015; NPIC 2015).
A review by WHO reported that glyphosate was not detected in cereal grains at harvest when application
of the herbicide occurred before planting (WHO 2005). Glyphosate was detected in cereals at mean
residue levels of 0.2–4.8 mg/kg when application of the herbicide was prior to harvesting. In one
assessment, levels of glyphosate were found to decrease upon industrial processing grains to flour from
1.6 to 0.16 mg/kg (WHO 2005). In wheat treated with either Glyfos or Roundup® herbicides, levels of
glyphosate were also found to decrease upon processing grains to flour from 0.28–1.0 mg/kg in the grains
to <0.05 mg/kg in the flour (FAO 2005). Glyphosate residues in oats stored at room temperature
compared to frozen storage were similar, 3.5 and 3.1 mg/kg, respectively (FAO 2005). After exposure to
glyphosate at 10 mg/L for 14 days, fish concentrations ranged from 0.2 to 0.7 mg/kg and decreased upon
exposure to glyphosate-free water (WHO 2005).
GLYPHOSATE 194
A review by Williams et al. (2000) reported U.S. glyphosate residue data for wheat treated with
maximum rates of Roundup®. Wheat crop residues consisted of a mean glyphosate concentration of
0.69 µg/g (mg/kg), with a maximum concentration of 2.95 µg/g (mg/kg). Glyphosate-tolerant soybeans
treated with maximum rates of Roundup® showed a mean glyphosate concentration of 2.36 µg/g (mg/kg)
and a maximum concentration of 5.47 µg/g (mg/kg).
Glyphosate was detected in carrot samples at average concentrations of 0.078±0.002 mg/kg and in
spinach at 0.104±0.005 mg/kg (Zhao et al. 2011).
Glyphosate residues were examined on alder and salmonberry foliage and leaf litter sprayed with
glyphosate at 2.0–2.1 kg/ha (Feng et al. 1990b). Foliar residues on alder and salmonberry were 261 and
448 ppm (dry weight), respectively, after the initial application of the herbicide. Leaf litter of alder and
salmonberry collected 15 days post-application had glyphosate residues of 12.5 and 19.2 ppm (mg/kg),
respectively. After 8–9 days, 50% dissipation was reported for the glyphosate residue. AMPA residues
in the leaf litter decreased, and at 29 days after application of the herbicide, concentrations of AMPA
were not detected.
The main routes of exposure to glyphosate for the general public result from the ingestion of foods with
residues of glyphosate and foods made from these crops, as well as dermal, ocular, or inhalation exposure
from application of herbicides containing glyphosate (EPA 2009c). Glyphosate has been detected in dust
samples from homes near glyphosate application sites or from people who brought it indoors on their
bodies and/or clothing from glyphosate-treated areas (Curwin et al. 2005). Additionally, pesticide
application equipment, such as backpack sprayers, may leak, causing workers to be dermally exposed to
glyphosate formulations (NIOSH 2017). Upon dermal exposure, absorption through the skin is expected
to be low based on dermal absorption studies, where an estimated 0.8–2.2% percutaneous absorption of
glyphosate occurred in a study using 14C-radiolabeled glyphosate in Roundup® (Wester et al. 1991).
Evidence has shown that proper hygiene removes glyphosate from skin and will deter absorption through
the skin (Wester et al. 1991). Limited monitoring data indicate that oral exposure may occur from
drinking contaminated well water supplied from groundwater contaminated with glyphosate;
concentrations reported in groundwater are relatively low, and this chemical has low leaching potential
from soil to groundwater. Exposure may also occur via ingestion of food with herbicidal residues
containing glyphosate as a result of its application. The FDA has not performed a total diet study on
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glyphosate. Glyphosate has not been included in the FDAs Pesticide Residue Monitoring Program
Reports for the fiscal years 2009 through 2015 (FDA 2013a, 2013b, 2014, 2015, 2016, 2017); however,
the FDA in 2016 and 2017 began preliminary testing of samples of soybeans, corn, milk, and eggs for
glyphosate residues (FDA 2018). Preliminary results showed no pesticide residue violations for
glyphosate in all four commodities tested (soybeans, corn, milk, and eggs). The Joint FAO/WHO
Meeting on Pesticide Residues listed International Estimated Daily Intake (IEDI) of glyphosate from 17
GEMS/Food (Global Environment Monitoring System-Food Contamination Monitoring and Assessment
Programme) cluster diets to range from 140.5 to 443.0 µg/person (FAO and WHO 2016). Glyphosate is a
non-volatile compound, and drift of herbicidal sprays may occur with aerial and ground equipment (Yates
et al. 1978); therefore, some exposure via inhalation and direct contact with skin and eyes may occur after
members of the general population apply glyphosate during residential use. Although the effects of
glyphosate exposure of populations living in areas where glyphosate-containing products have been
aerially-applied to eradicate coca crops have been evaluated (Paz-y-Miño et al. 2007, 2011; Solomon et
al. 2009), such reports did not include monitoring of exposure levels.
Occupational exposure may occur in both forestry, landscaping, and agricultural settings from the direct
use of herbicides containing glyphosate. The most probable routes for occupational exposure are via
inhalation and dermal contact with this chemical at workplaces where glyphosate or products containing
this chemical are produced or used. Oral exposure may occur from accidental ingestion. During the
years 1990–1993, exposure to glyphosate of field workers applying mixtures of Roundup® plus an
additional herbicide in areas of Louisiana was assessed (LaDOTD 1995). Mixtures of Roundup® (active
ingredient glyphosate) plus Garlon-3A (active ingredient triclopyr) and Roundup® (active ingredient
glyphosate) plus 2,4-D (active ingredient 2,4-dichlorophenoxyacetic acid) were applied by 13 workers
using spray equipment with operating capabilities of 0.37 L/minute. Glyphosate was detected in the
workers’ urine using HPLC with a detection limit of 100 ppb. Total excreted urinary amounts of
glyphosate ranging from non-detectable to 175 µg/day were reported for both working and non-working
days. Urine concentrations were higher than concentrations found in the collected air samples of the
breathing zone. It was noted that inhalation exposure was very low compared with threshold limits; the
maximum air concentration was 17.9 µg/m3. Dermal contact and improper hygiene leading to ingestion
of the herbicides were noted as the probable routes of exposure.
One-hundred adults older than 50 years who resided in Southern California, as part of the Rancho
Bernardo study, were sampled for glyphosate and its metabolite AMPA in 1993-1996 and again in 2014-
2016 (Mills et al. 2017). The study did not indicate that any of these adults were involved in application
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of pesticides containing glyphosate. In 1993-1996, only 12 participants had glyphosate above the level of
detection (LOD=0.03 µg/L) in urine and mean levels were 0.024 for all participants, and 5 participants
had detected levels of AMPA (LOD=0.04 µg/L) with the mean levels of 0.008 µg/L for all participants.
By 2014-2016 sampling, 70/100 participants had detectable levels of glyphosate and 71/100 of AMPA.
Means levels in all 100 participants were 0.314 µg/L and 0.285 µg/L for glyphosate and AMPA,
respectively (Mills et al. 2017).
Farmers, with an average age of 45 years licensed as pesticide applicators in South Carolina and
Minnesota, who applied herbicides containing glyphosate had average urinary glyphosate levels of 3 µg/L
on the day of application (Acquavella et al. 2004). Lack of wearing rubber gloves was associated with
higher concentrations in farmers’ urine. Spouses, with an average age of 42.2 years residing with the
farmers but having minimal or no involvement in the preparation or application of the herbicide, had
relatively low and consistent urine concentrations of glyphosate, while children (ages 4–18 years) had an
increase followed by a decrease in urine concentrations correlated with application (see Table 5-11). For
the entire assessment period, 88–95% of all samples of children’s urine were below the detection limit (1
µg/L [ppb] for a 100-mL urine sample). Farmers applying the pesticide had the highest concentrations.
The highest concentration of glyphosate found in a child was from a teenage male (29 µg/L [ppb]) who
had assisted with mixing and application of the herbicide. An estimated dermal and inhalation exposure
value of about 8,000 μg/hour was reported as the highest value from a study of workers employing spray
applicators; when corrected for incomplete absorption, this corresponds to an approximate exposure of
50 μg/kg body weight/day (8-hour working day for a 70-kg adult) (IPCS 1994).
Concentrations/
Medium minimum, maximum Average Notes Reference
Tissue Postmortem, Glyphosate (ppm): After one individual Menkes et
(brain, approximately 12– kidney 3,650; liver ingested 200–250 mL al. 1991
blood, 13 hours after 600; blood; 550; brain; Roundup® with 72–
liver, ingestion 100 91 g/mL glyphosate
kidney)
Urine Pre-application <1–15 µg/L (ppb) Not reported Farmers applying Acquavella
Day of pesticide <1–233 µg/L (ppb) Geometric pesticide; average age: et al. 2004
application mean: 45 years
3.2 µg/L (ppb)
1-Day post- <1–126 µg/L (ppb) Geometric
pesticide application Mean:
1.7 µg/L (ppb)
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Concentrations/
Medium minimum, maximum Average Notes Reference
2-Day post- <1–81 µg/L (ppb) Geometric
pesticide application mean:
1.1 µg/L (ppb)
3-Day post- <1–68 µg/L (ppb) Geometric
pesticide application mean:
1.0 µg/L (ppb)
Pre-application <1–3 µg/L (ppb) Not reported Spouses not involved
Day of pesticide <1–2 µg/L (ppb) Not reported with application;
application average age: 42 years
1–3-Day post- <1–1 µg/L (ppb) Not reported
pesticide application
Pre-application <1–17 µg/L (ppb) Not reported Children not involved
Day of pesticide <1–29 µg/L (ppb) Not reported with application;
application average age:
11.5 years
1-Day post- <1–24 µg/L (ppb) Not reported
pesticide application
2-Day post- <1–12 µg/L (ppb) Not reported
pesticide application
3-Day post- <1–6 µg/L (ppb) Not reported
pesticide application
Daily during 1-week <0.1 ng/µL Forest workers using Jauhiainen
working period pressurized herbicide et al. 1991
3 Weeks after <0.1 ng/µL sprayers; 8%
1-week working Roundup® (active
period ingredient 360 g/L
isopropylamine salt)
General population Not reported 0.024 µg/L Adults >50 years of
exposure (ppb) age not involved in
application in 1993-
1996 Mills et al.
General population Not reported 0.314 µg/L Adults involved in 2017
exposure (ppb) application in 2014-
2016; average age:
77.7 years
Following mild to Glyphosate: 228 mg/L 13 individuals ages 25– Zouaoui et
fatal ingestions of mild/moderate case; 69 years al. 2013
20–500 mL 22,300 mg/L fatal
pesticide case; AMPA:
0.54 mg/L
mild/moderate case;
91.5 mg/L fatal case
Two occasions 0.13–5.4 µg/L 1.4 µg/L Farm fathers Curwin et al.
(1 month apart) 0.20–18 µg/L 1.9 µg/L Non-farm fathers 2007b
during spring and
0.062–5.0 µg/L 1.2 µg/L Farm mothers
0.10–11 µg/L 1.5 µg/L Nonfarm mothers
GLYPHOSATE 198
Concentrations/
Medium minimum, maximum Average Notes Reference
summer of 2001 0.10–9.4 µg/L 2.7 µg/L Farm children
(LOD 0.9 µg/L) 0.022–18 µg/L 2 µg/L Non-farm children
Blood Following mild to Glyphosate: 3.7 mg/L Zouaoui et
fatal ingestions of mild/moderate case; al. 2013
20–500 mL 6,640 mg/L fatal case;
pesticide AMPA: 0.13 mg/L
mild/moderate case;
15.4 mg/L fatal case
Acquavella et al. (1999) evaluated 1,513 reported cases to the American Association of Poison Control
Centers during the years 1993–1997 of ocular or dermal/ocular exposure to Roundup® herbicides with
glyphosate concentrations ranging from <2 to >20%. Of all exposure cases, 62% involved male subjects,
>80% were in a residential setting, and about 15% were in occupational settings. During the time period,
California and Texas had the greatest number of reported cases. Dilute Roundup® formulations
accounted for about 82% of the exposures; 5% were with concentrated Roundup®.
Acquavella et al. (2005) analyzed biomonitoring data of farmers before, during and after pesticide
application and para-occupational exposure to their spouses and children over a course of five days (1 day
before, 1 day during and 3 days post-exposure). Glyphosate was measured in urine at a peak of 3 ppb
(LOD 1 ppb) on the day of application and then decreased rapidly. Among the spouse and children of
farmers, glyphosate urinary levels remained relatively stable with only appreciable changes in
concentration after exposure to pesticide application.
Brouwer et al. (2016) pooled exposure data from three agriculture cohorts from USA, France and
Norway, specifically, the Agricultural Health Study (AHS), Agriculture and Cancer Study (AGRICAN)
and the Cancer in the Norwegian Agricultural Population (CNAP), respectively. Among 316,270
participants who were pesticide applicators or farmers (active or retired), 99% reported ever using any
pesticide of which 44% reported to have ever been exposed to glyphosate, ranging between 1 to 21 years
of exposure. Specifically, 129,327 men (54%) and 41,276 (14%) females were exposed to glyphosate
across the three cohorts.
Aris and LeBlanc (2011) examined blood concentrations of glyphosate in a group of 30 pregnant and
39 non-pregnant females residing in Sherbrooke, Canada. The study noted that none of the subjects
GLYPHOSATE 199
worked or lived with an individual who worked with pesticides. Neither glyphosate nor AMPA were
detected in the maternal or fetal cord serum of pregnant subjects. Additionally, AMPA was not detected
in non-pregnant subjects. Glyphosate was detected in 5% of the non-pregnant subjects at a range of not
detectable to 93.6 ng/mL, with a mean of 73.6 ng/mL (LOD=15 ng/mL).
The Fourth National Report on Human Exposures to Environmental Chemicals, published and updated by
the Centers for Disease Control and Prevention reporting biomonitoring data from the National Health
and Nutrition Examination Survey (NHANES), does not include data for glyphosate or its metabolite,
AMPA (CDC 2019).
As with the adult general population, exposure of children to glyphosate may occur through ingestion of
foods with residues of glyphosate and foods made from these crops, as well as inhalation, dermal contact,
and/or ocular contact when in the proximity of areas where glyphosate containing herbicides have been
recently applied. Glyphosate has been detected in dust samples from homes near glyphosate application
sites or from people who brought it indoors on their bodies and/or clothing from glyphosate-treated areas
(Curwin et al. 2005). Limited monitoring data indicate that oral exposure may occur from drinking
contaminated well water supplied from groundwater contaminated with glyphosate; concentrations
reported in groundwater are relatively low, and this chemical has low leaching potential from soil to
groundwater. It is unclear if breastmilk is a route of exposure for glyphosate as there are only two studies
which have evaluated this route (Bus 2015 and McGuire et al., 2016). According to Bus (2015)
glyphosate is not likely to bioaccumulate in breast milk and McGuire et al., 2016 did not detect it in
breast milk from lactating mothers with detectable glyphosate in their urine (McGuire et al. 2016).
During the spring and summer of 2001, urinary pesticide concentrations were investigated in families
residing in non-farm and farm households located in Iowa (Curwin et al. 2007a, 2007b). Urinary
glyphosate levels were fairly similar between farm and non-farm households. In addition, glyphosate
concentrations were fairly similar when comparing individuals living on farms where the pesticide was
used with those living on farms where the pesticide was not used. Glyphosate was detected at urinary
levels equal to or greater than the LOD (0.9 µg/L) in 66% of the 23 non-farm fathers, 75% of the 24 farm
fathers, 65% of the 24 non-farm mothers, 67% of the farm mothers, 88% of the non-farm children, and
81% of the farm children (Curwin et al. 2007b). Estimated glyphosate intakes among 40 children
(17 homes) living on farms where glyphosate was applied ranged from 0.001 to 0.33 µg/kg/day, with 16%
of the samples below the LOD (Curwin et al. 2007a). Estimated glyphosate intakes among 25 children
GLYPHOSATE 200
(8 homes) living on farms where glyphosate was not applied ranged from 0.003 to 0.64 µg/kg/day, with
20% of the samples below the LOD.
McQueen et al. (2012) estimated the mean glyphosate dietary exposure of 43 pregnant women at
0.001 mg/kg body weight/day and these exposures were well below applicable health guidelines. Since
only a small percentage of glyphosate crosses the placenta, fetal exposure resulting from maternal
exposure to glyphosate was minimal.
Farm workers, farming families, landscaping workers, and people of all ages living and or working in
agricultural sectors will incur higher exposure to glyphosate, as agriculture is the largest industry for
herbicide use. Field workers who apply herbicides containing glyphosate will likely incur higher
exposures to this chemical. Levels of glyphosate in field workers’ urine has been shown to increase
during spraying season; however, glyphosate levels did not appear to carry over from previous seasons
(LaDOTD 1995).
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Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the
Administrator of EPA and agencies and programs of the Public Health Service) to assess whether
adequate information on the health effects of glyphosate is available. Where adequate information is not
available, ATSDR, in conjunction with NTP, is required to assure the initiation of a program of research
designed to determine the adverse health effects (and techniques for developing methods to determine
such health effects) of glyphosate.
Data needs are defined as substance-specific informational needs that, if met, would reduce the
uncertainties of human health risk assessment. This definition should not be interpreted to mean that all
data needs discussed in this section must be filled. In the future, the identified data needs will be
evaluated and prioritized, and a substance-specific research agenda will be proposed.
Studies evaluating the health effects of inhalation, oral, and/or dermal exposure of humans and animals to
glyphosate that are discussed in Chapter 2 are summarized in Figure 6-1 for glyphosate technical and
Figure 6-2 for glyphosate formulations. As described in Chapter 2, data on inhalation and dermal
exposure to glyphosate technical were limited. Therefore, Figure 6-1 only summarizes oral exposure
studies. The purpose of these figures is to illustrate the information concerning the health effects of
glyphosate. The number of human and animal studies examining each endpoint is indicated regardless of
whether an effect was found and the quality of the study or studies.
The health effects of glyphosate have been evaluated in epidemiology and animal studies.
Epidemiological studies are predominantly case-control and cohort epidemiology studies that examined
possible associations between glyphosate exposure and selected health outcomes (noncancer and cancer
endpoints), or case reports following accidental or intentional ingestion of glyphosate-containing
products. These studies do not include data regarding the extent of the exposure or relative contribution
of inhalation, oral and/or dermal exposure. Most health effects data come from animal studies that
employed oral exposure and examined potential body weight, gastrointestinal, hematological, hepatic,
and/or developmental effects.
GLYPHOSATE 202
*Includes studies discussed in Chapter 2; the numbers of studies include those finding no effect.
GLYPHOSATE 203
Missing information in Figure 6-1 and Figure 6-2 should not be interpreted as a “data need”. A data need,
as defined in ATSDR’s Decision Guide for Identifying Substance-Specific Data Needs Related to
Toxicological Profiles (ATSDR 1989), is substance-specific information necessary to conduct
comprehensive public health assessments. Generally, ATSDR defines a data gap more broadly as any
substance-specific information about glyphosate technical missing from the scientific literature.
Therefore, uncertainties with regard to glyphosate-based formulations (GBFs) would not be considered a
data gap for the purposes of this Profile. However, exposure to GBFs is widespread, and studies
investigating the toxicity and components of the individual GBFs are important. EPA’s 2016 Glyphosate
Issue Paper states, “additional research could also be performed to determine whether formulation
components, such as surfactants, influence the toxicity of glyphosate formulations,” and describes plans
to investigate the potential toxicity of GBF components (EPA 2016c).
Oral studies in animals indicate that glyphosate technical toxicity is associated with oral doses levels
many times higher than levels allowed as residues in food products. The general population is most likely
to be exposed to glyphosate residues in food sources. Humans should continue to be monitored for
possible associations between glyphosate intake from food sources and adverse health outcomes.
Individuals can also be exposed to glyphosate via inhalation, dermal contact, and/or ocular contact during
application of the herbicide or by being in the vicinity where it is applied. However, available dermal
studies indicate that only 3–4% of dermally-applied glyphosate enters the blood, though local dermal
toxicity is possible (see Section 2.11). Data regarding the extent of absorption and potential health effects
following inhalation exposure are lacking. Therefore, human and animal studies should be designed to
evaluate airborne exposure levels and possible health effects from inhalation exposure. Additional animal
studies should be designed to assess the toxic effects of exposure to a variety of glyphosate formulations
and individual components suspected to be toxic. Such studies could also be designed to evaluate
possible interactions among individual components that might enhance toxicity.
Acute-, Intermediate-, and Chronic-Duration MRLs. No inhalation MRLs were derived for
glyphosate due to the lack of quantitative exposure-response data for humans or animals.
As stated previously, most information is available from animal studies submitted to EPA’s Office of
Pesticides Programs using glyphosate technical (typically >90% purity) to fulfill requirements for the
registration of a particular glyphosate formulation for use in the United States. Some animal studies in
GLYPHOSATE 205
the open literature used glyphosate formulations that typically included 1–41% glyphosate technical (or
glyphosate salts) and up to 18% surfactant (along with other “inert” ingredients). Surfactants in
glyphosate formulations may be at least partly responsible for the toxic effects from overexposure to
glyphosate formulations (Adam et al. 1997; Sawada et al. 1988; Williams et al. 2000). Human exposure
to glyphosate formulations via its use in weed control includes exposure to all substances in a particular
glyphosate formulation as well as to other substances that may be added by the end user. No MRLs were
derived for glyphosate formulations due to the wide variation in glyphosate content and surfactants used
in various glyphosate formulations and the fact that surfactants can contribute to the toxicity of
glyphosate formulations. However, because exposures of the general population via food or water
sources with measurable glyphosate residues most likely involve glyphosate and/or its breakdown
products rather than the intact glyphosate-based formulation, health effects data associated with oral
exposure to glyphosate technical are considered relevant to potential derivation of oral MRLs for
glyphosate. Oral MRLs based on glyphosate technical would not be applicable to intentional or
accidental ingestion of a glyphosate formulation.
Acute- and chronic-duration oral MRLs were derived for glyphosate based on gastrointestinal effects in
animal studies. The chronic-duration oral MRL was adopted as the intermediate-duration oral MRL.
Health Effects
Respiratory. Limited information was located regarding the effects of inhalation exposure in
laboratory animals. A single 4-week repeated-exposure rat study found no effects at the highest
exposure concentration tested (36 mg Roundup®/m3). Studies should be designed to evaluate
respiratory effects in animals exposed to glyphosate by inhalation.
Epidemiology and Human Dosimetry Studies. Limited information was located regarding
respiratory effects associated with human exposure to glyphosate-based formulations. Additional studies
GLYPHOSATE 206
should be designed to monitor exposure levels and health effects associated with individuals involved in
the application of glyphosate-based products. There is limited evidence for glyphosate-related
developmental effects in humans. Additional studies should be designed to evaluate possible associations
between exposure to glyphosate and developmental endpoints in humans. Numerous agencies have
evaluated glyphosate for possible associations between exposure and risk of various cancers. The
majority of the human studies used self-reported ever/never glyphosate use as the biomarker of exposure.
The results of these studies should be interpreted cautiously given the lack of quantitative or semi-
quantitative glyphosate exposure information and the likely exposure to other pesticides. Most studies
found no association between exposure to glyphosate-based products and risk of cancer. However, a
possible association between exposure to glyphosate and risk of non-Hodgkin’s lymphoma could not be
ruled out, based on conflicting results.
Biomarkers of Exposure and Effect. The most reliable biomarker of exposure to glyphosate is its
detection in blood and urine. However, the limit of detection (LOD) for glyphosate in blood is higher than
the LOD for glyphosate in urine (see Table 5-4), meaning using urine as a biomarker of exposure may be
more informative, especially in cases where human glyphosate levels are expected to be low. Recent
biomarker studies seem to show a preference for urine as a biomarker (Soukup et al. 2020, Zoller et al.
2020, Zhang et al. 2020).
Physical and Chemical Properties. The physical chemical properties of glyphosate are
summarized in Chapter 4. No data needs are identified.
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Production, Import/Export, Use, Release, and Disposal. No information is available in the TRI
database on facilities that manufacture or process glyphosate because this chemical is not required to be
reported under Section 313 of the Emergency Planning and Community Right-to-Know Act (Title III of
the Superfund Amendments and Reauthorization Act of 1986) (EPA 2005b). There is no information on
releases of glyphosate from manufacturing and processing facilities because these releases are not
required to be reported (EPA 2005b). Data on current manufacturing, processing, import/export values
would be useful information. Data on current uses and disposal practices are outlined in Sections 5.2.3
and 5.2.4. Further studies on these practices do not appear to be essential.
Environmental Fate. Transport, partitioning, and bioconcentration data are available for glyphosate
summarized in Section 5.4. In glyphosate-tolerant plants, glyphosate is converted to N-acetylglyphosate;
therefore, studies evaluating the possibility of additional crop and plant metabolites, along with the
characteristic fates, may be beneficial (Pioneer 2006). Additional studies should be designed to further
assess potential for glyphosate to persist in foods, water, and soil.
Bioavailability from Environmental Media. Glyphosate degrades quickly in the environment and
adsorbs to soils and sediment and possesses low bioconcentration in aquatic organisms, suggesting that
bioavailability from environmental media is low. A study regarding the bioavailability of glyphosate in
soil indicated that degradation rates decreased in lower soil horizons as microbial populations of
glyphosate degrading organisms decreased, but bioremediation practices that incorporate anthropic
bacteria can be useful to remediate highly polluted glyphosate-containing soils and maintain low
bioavailability (Shushkova et al. 2010). Additional studies on glyphosates bioavailability from different
types of soil would be helpful to expand our understanding of potential human exposures to glyphosate
bound residues.
Food Chain Bioaccumulation. Studies are available that indicate that glyphosate has very low
potential to bioconcentrate in aquatic organisms and is not expected to bioaccumulate in the food chain.
No data needs are identified.
Exposure Levels in Environmental Media. Reliable monitoring data for the levels of glyphosate
in environmental media surrounding areas where it is applied are available (Chang et al. 2011; USGS
2007; WQP 2017). The USGS NAWQA frequently reports on levels of glyphosate and other substances
GLYPHOSATE 208
in both surface water and groundwater. No data needs are identified; however, monitoring studies in air,
water, soil, and other environmental media should continue as this is an herbicide used globally.
Exposure Levels in Humans. Studies are needed to investigate human intake of glyphosate via
food and water, such as total diet studies. Up until 2016–2017, the FDA did not test for glyphosate
residues in food sources because its multi-residue testing protocols did not include glyphosate. The FDA
has now developed a method to specifically test for glyphosate residues in foods and results are expected
to be provided through the FDA Pesticide Residue Monitoring Program (FDA 2018). Biomonitoring
information of glyphosate for the general population would be useful in conducting future risk
assessments.
Analytical Methods. Standardized methods that yield low detection limits for glyphosate and
aminomethylphosphonic acid (AMPA) in biological samples (e.g., urine analysis, blood analysis) may
provide more sensitivity and a more complete exposure analysis.
Pertinent international and national regulations, advisories, and guidelines regarding glyphosate in air,
water, and other media are summarized in Table 7-1. This table is not an exhaustive list, and current
regulations should be verified by the appropriate regulatory agency.
ATSDR develops MRLs, which are substance-specific guidelines intended to serve as screening levels by
ATSDR health assessors and other responders to identify contaminants and potential health effects that
may be of concern at hazardous waste sites. See Section 1.3 and Appendix A for detailed information on
the MRLs for glyphosate.
aEPA’s Office of Pesticides Program (OPP) published an interim registration review decision on glyphosate in
January 2020, which finalized the Glyphosate Draft Human Health Risk Assessment in Support of Registration
Review. The human health risk assessment derived an RfD of 1.0 mg/kg/day based on the same study that ATSDR
used for derivation of the acute-duration MRL.
bGlyphosate and aminomethylphosphonic acid occur in drinking water at concentrations well below those of health
ACGIH = American Conference of Governmental Industrial Hygienists; AEGL = acute exposure guideline levels;
CFR = Code of Federal Regulations; DOE = Department of Energy; DWEL = drinking water equivalent level;
EAFUS = Everything Added to Food in the United States; EPA = Environmental Protection Agency; FDA = Food and
Drug Administration; HHS = Department of Health and Human Services; IARC = International Agency for Research
on Cancer; NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology Program;
OSHA = Occupational Safety and Health Administration; PAC = Protective Action Criteria; PEL = permissible
exposure limit; REL = recommended exposure limit; RfC = inhalation reference concentration; RfD = reference dose
TLV = threshold limit values; TWA = time-weighted average; WHO = World Health Organization
GLYPHOSATE 212
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GLYPHOSATE A-1
MRLs are derived when reliable and sufficient data exist to identify the target organ(s) of effect or the
most sensitive health effect(s) for a specific duration for a given route of exposure. An MRL is an
estimate of the daily human exposure to a hazardous substance that is likely to be without appreciable risk
of adverse noncancer health effects over a specified route and duration of exposure. MRLs are based on
noncancer health effects only; cancer effects are not considered. These substance-specific estimates,
which are intended to serve as screening levels, are used by ATSDR health assessors to identify
contaminants and potential health effects that may be of concern at hazardous waste sites. It is important
to note that MRLs are not intended to define clean-up or action levels.
MRLs are derived for hazardous substances using the NOAEL/uncertainty factor approach. They are
below levels that might cause adverse health effects in the people most sensitive to such chemical-
induced effects. MRLs are derived for acute (1–14 days), intermediate (15–364 days), and chronic
(≥365 days) durations and for the oral and inhalation routes of exposure. Currently, MRLs for the dermal
route of exposure are not derived because ATSDR has not yet identified a method suitable for this route
of exposure. MRLs are generally based on the most sensitive substance-induced endpoint considered to
be of relevance to humans. Serious health effects (such as irreparable damage to the liver or kidneys, or
birth defects) are not used as a basis for establishing MRLs. Exposure to a level above the MRL does not
mean that adverse health effects will occur.
MRLs are intended only to serve as a screening tool to help public health professionals decide where to
look more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that
are not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of
the lack of precise toxicological information on the people who might be most sensitive (e.g., infants,
elderly, nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR
uses a conservative (i.e., protective) approach to address this uncertainty consistent with the public health
principle of prevention. Although human data are preferred, MRLs often must be based on animal studies
because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes
that humans are more sensitive to the effects of hazardous substance than animals and that certain persons
may be particularly sensitive. Thus, the resulting MRL may be as much as 100-fold below levels that
have been shown to be nontoxic in laboratory animals.
GLYPHOSATE A-2
APPENDIX A
Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the
Division of Toxicology and Human Health Sciences, expert panel peer reviews, and agency-wide MRL
Workgroup reviews, with participation from other federal agencies and comments from the public. They
are subject to change as new information becomes available concomitant with updating the toxicological
profiles. Thus, MRLs in the most recent toxicological profiles supersede previously published MRLs.
For additional information regarding MRLs, please contact the Division of Toxicology and Human
Health Sciences, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road NE, Mailstop
S102-1, Atlanta, Georgia 30329-4027.
Human exposure to glyphosate formulations via its use in weed control includes exposure to all
substances in a particular glyphosate formulation. No MRLs were derived for glyphosate formulations
due to the wide variation in glyphosate content and surfactants used in various glyphosate formulations
and the fact that surfactants can contribute to the toxicity of glyphosate formulations. However, the
general population may be exposed via food or water sources containing glyphosate residues from
glyphosate-based formulations registered for use in agricultural and residential environments. Therefore,
health effects data associated with oral exposure to glyphosate technical are considered relevant to
potential derivation of oral MRLs for glyphosate.
GLYPHOSATE A-3
APPENDIX A
MRL Summary: There are insufficient data for derivation of an acute-duration inhalation MRL.
Rationale for Not Deriving an MRL: No acute-duration inhalation exposure-response studies were
identified for glyphosate.
APPENDIX A
MRL Summary: There are insufficient data for derivation of an intermediate-duration inhalation MRL.
APPENDIX A
MRL Summary: There are insufficient data for derivation of a chronic-duration inhalation MRL.
Rationale for Not Deriving an MRL: No chronic-duration inhalation exposure-response studies were
identified for glyphosate.
APPENDIX A
MRL Summary: An acute-duration oral MRL of 1 mg/kg/day was derived for glyphosate based on
gastrointestinal effects (diarrhea, few feces) observed in pregnant female New Zealand white rabbits
administered glyphosate acid (96.5% purity) by daily gavage (in deionized water) during GDs 8–20
(EPA 2017b). The MRL is based on a NOAEL of 100 mg/kg/day and a total uncertainty factor of 100
(10 for animal to human extrapolation and 10 for human variability).
Selection of the Critical Effect: Several acute-duration oral studies were available regarding the toxicity
of glyphosate technical following acute-duration oral exposure (see Table A-1). The lowest LOAELs
were 175 mg/kg/day for gastrointestinal effects (diarrhea, few feces) in maternal rabbits and
300 mg/kg/day for developmental effects (depressed fetal weight) following gavage treatment with
glyphosate technical during GDs 8–20 at 175 mg/kg/day. Based on available data, gastrointestinal
disturbance is considered to represent the most sensitive effect of glyphosate toxicity following oral
exposure in laboratory animals.
NOAEL LOAEL
Endpoint Effect (mg/kg/day) (mg/kg/day) Reference
Body weight 28.5% depressed maternal body weight 1,000 3,500 EPA 1992e
gain in rats
No effect in pregnant rats 1,000 EPA 2017b
No effect in pregnant rabbits 300 EPA 2017b
Gastrointestinal Diarrhea in 2/8 rats gavaged once 2,000 Adam et al. 1997
Diarrhea in rats gavaged once 1,000 2,000 EPA 2013c
Diarrhea, soft stools in pregnant rats 1,000 3,500 EPA 1992e
gavaged on GDs 6–19
Diarrhea, few feces in pregnant rabbits 100 175 EPA 2017b
gavaged on GDs 8–20
GLYPHOSATE A-7
APPENDIX A
NOAEL LOAEL
Endpoint Effect (mg/kg/day) (mg/kg/day) Reference
Developmental Decreased fetal weight; delayed 1,000 3,500 EPA 1992e
ossification
No effect in fetuses from pregnant rats 1,000 EPA 2017b
gavaged on GDs 7–16
Depressed weight in fetuses from 175 300 EPA 2017b
pregnant rabbits gavaged on GDs 8–20
Other Hypothermia in rats gavaged once 1,000 2,000 EPA 2013c
Selection of the Principal Study: Among available acute-duration oral toxicity studies for glyphosate,
the developmental toxicity study in rabbits (EPA 2017b) identified the lowest LOAEL (gastrointestinal
effects in pregnant rabbits gavaged with glyphosate acid); the corresponding NOAEL was 100 mg/kg/day.
Therefore, this study was selected as the principal study for deriving an acute-duration oral MRL for
glyphosate.
EPA. 2017b. Memorandum. December 13, 2017. Glyphosate: Preparation of data evaluation records
for developmental rat and rabbit toxicity studies. MRID No.: 43320615, 43320616. Washington, DC:
U.S. Environmental Protection Agency, Office of Chemical Safety and Pollution Prevention.
Groups of sperm-positive female New Zealand white rabbits (20/group) were administered glyphosate
acid (95.6% active ingredient) by daily gavage (in deionized water vehicle; dosing volume 2 mL/kg body
weight) on GDs 8–20 at target concentrations of 0, 100, 175, or 300 mg/kg/day (adjusted for purity of
active ingredient). Dams were monitored for survival, clinical signs, body weight, and food intake. On
GD 30, dams were sacrificed and subjected to gross external and internal examination, pregnancy status,
weight of gravid uteri, number of corpora lutea, number and position of implantations, live fetuses, and
early and late intrauterine deaths. Fetuses were evaluated for weight and sex. External, visceral, and
skeletal examinations were performed; brains were subjected to macroscopic examination.
The 100 mg/kg/day dose level represented a NOAEL for maternal toxicity. At 175 and 300 mg/kg/day,
maternal rabbits exhibited diarrhea and reduced production of feces. Mean body weight in the
300 mg/kg/day group of maternal rabbits ranged from 5.2 to 7.4% less than that of controls during
GDs 16–26. The depressed maternal body weight was <10% in magnitude, and was therefore not
considered to represent an adverse effect. Furthermore, there were no statistically significant differences
between controls and glyphosate-treated groups regarding GD 30 mean maternal body weight. Gross
pathologic examination of maternal rabbits revealed no treatment-related effects. There were no
treatment-related effects on pregnancy rate, numbers of corpora lutea, total number of implantation sites,
litter size, sex ratio, or pre- or post-implantation loss. The 300 mg/kg/day dose group exhibited 8.3%
lower mean fetal weight (p<0.05). Gross and visceral examination of fetuses revealed no treatment-
related effects. Increased incidences of fetuses with selected minor skeletal defects (e.g., delayed
sternebral and vertebral ossification) were observed at the 300 mg/kg/day maternal dose level. However,
incidences of these skeletal defects did not appear to be increased in glyphosate-treated groups when
GLYPHOSATE A-8
APPENDIX A
evaluated on a per litter basis; therefore, they were not considered treatment-related developmental
effects.
Selection of the Point of Departure: Incidence data for the gastrointestinal effects were not presented in
the available data evaluation record (DER) for the study, thus precluding a benchmark dose (BMD)
approach to deriving an MRL. Therefore, the NOAEL of 100 mg/kg/day was selected as the point of
departure for deriving an acute-duration oral MRL for glyphosate.
Uncertainty Factor: The NOAEL of 100 mg/kg/day was divided by a total uncertainty factor of 100:
• 10 for animal to human extrapolation
• 10 for human variability
APPENDIX A
MRL Summary: The chronic-duration oral MRL of 1 mg/kg/day is adopted as the intermediate-duration
oral MRL.
Rationale for Not Deriving an MRL: Several intermediate-duration oral animal studies were available
for glyphosate technical (see Table A-2).
NOAEL LOAEL
Endpoint Effect (mg/kg/day) (mg/kg/day) Reference
Body weight 12–18% depressed paternal body M: 754 M: 2,219 EPA 1992a
weight gain in rats F: 802 F: 3,134
No effect in rats (highest dose) M, F: 30 EPA 1992g
No effect in rats (highest dose) M: 1,234 EPA 2013a
F: 1,273
18% lower mean body weight and M: 1,678 M: 3,393 NTP 1992
body weight gain in male rats F: 3,393
No effect in mice (highest dose) F: 1,447.5 EPA 2013b
10–11% lower mean final body M: 2,273 M: 4,776 NTP 1992
weight in mice F: 5,846 F: 11,977
No effect in maternal rabbits F: 350 EPA 1992f
(highest dose)
Gastrointestinal Soft stool in rats M: 754 M: 2,219 EPA 1992a
F: 802 F: 3,134
Increased severity of basophilia M: 205 M: 410 NTP 1992
and hypertrophy of acinar cells in F: 213 F: 421
parotid and submandibular salivary
glands of rats
Increased severity of basophilia of M: 1,065 M: 2,273 NTP 1992
acinar cells in parotid salivary gland F: 1,411 F: 2,707
of mice
Increased incidence of soft stool 175 350 EPA 1992f
and/or diarrhea in pregnant rabbits
Hematological No effect in rats (highest dose) M, F: 3,393 NTP 1992
GLYPHOSATE A-10
APPENDIX A
NOAEL LOAEL
Endpoint Effect (mg/kg/day) (mg/kg/day) Reference
Hepatic No effect in rats (highest dose) M: 1,234 EPA 2013a
F: 1,273
M: Increases in liver weight and M: 811 M: 1,678 NTP 1992
serum ALT
F: Increases in liver weight and F: 1,690 F: 3,393
serum AP, ALT, and bile acids
No effect in mice M: 10,780 NTP 1992
F: 11,977
Renal No effect in rats (highest dose) M: 1,234 EPA 2013a
F: 1,273
Immunological No effect in mice (highest dose) F: 1,447.5 EPA 2013b
Neurological No effect in rats (highest dose) M: 1,546.5 EPA 2013c
F: 1,630.6
Reproductive No effect in rats (highest dose) M: 2,219 EPA 1992a
F: 3,234
No effect in rats (highest dose) M, F: 30 EPA 1992g
No effect in rats (highest dose) M: 1,234 EPA 2013a
F: 1,273
Developmental 14–20% depressed pup body 802 3,134 EPA 1992a
weight during lactation (maternally
toxic dose level)
Delayed preputial separation 408 1,234 EPA 2013a
No effect in rabbits (highest dose) 350 EPA 1992f
Increased incidence of kidney tubular dilation was reported for F3b male weanlings of a 3-generation
study of glyphosate technical (98.7% purity) administered to male and female Sprague-Dawley rats in the
diet at an estimated dose level of 30 mg/kg/day; the reported NOAEL was 10 mg/kg/day (EPA 1992g).
However, there were no signs of treatment-related effects on kidneys of rat offspring in two subsequent
2-generation rat studies at dietary doses up to 1,234 or 1,273 mg/kg/day for parental males and females,
respectively (EPA 2013a), or 2,633 or 3,134 mg/kg/day for parental males and females, respectively
(EPA 1992a). Therefore, the finding of increased incidence of kidney tubular dilation in the 3-generation
rat study (EPA 1992g) was considered a spurious result rather than a glyphosate-induced adverse
developmental effect. In one 2-generation oral rat study, exposure via the diet at estimated parental dose
levels of 1,234 or 1,273 mg/kg/day (parental males and females, respectively) resulted in delayed
preputial separation in male pups (EPA 2013a). In the other 2-generation study, the highest dietary dose
level (up to 2,633 and 3,134 mg/kg/day for parental males and females, respectively) resulted in up to 14–
20% depressed pup body weight and/or body weight gain during the lactation period (EPA 1992a). There
were no apparent treatment-related developmental effects in a study of rabbits treated by gavage at up to
350 mg/kg/day during GDs 6–27 (EPA 1992f).
GLYPHOSATE A-11
APPENDIX A
Consideration was given to the increased anogenital distance (AGD) reported by Manservisi et al. (2019).
This pilot study found that male F1 Sprague-Dawley rats exposed to 1.75 mg/kg/day glyphosate technical
from gestation day 6 to post-natal day 120 showed increased anogenital distance at postnatal day 4.
However, this result was determined to be insufficient for MRL derivation. The study used only one dose,
which was substantially lower than the other lowest observed adverse effect levels (LOAELs) and the no
observed adverse effect levels (NOAELs) identified in the body of literature. Furthermore, while
decreases in AGD are sometimes considered an adverse effect related to endocrine disruption, increases
in AGD are less commonly used because the toxicological significance of such increases is not well
understood (Schwartz et al. 2019). Given that only one dose was tested, the observed effect was small
(6%) and not observed in other studies, and because the relevance of such an effect to human health is not
well-understood, it is not appropriate to use this study for MRL derivation.
As shown in Table A-2, gastrointestinal endpoints are the most sensitive to intermediate-duration oral
exposure of laboratory animals to glyphosate technical. Pregnant rabbits gavaged with glyphosate
technical daily at 350 mg/kg/day (LOAEL) during GDs 6–27 exhibited increased incidence of soft stool
and/or diarrhea; the NOAEL was 175 mg/kg/day (EPA 1992f). Similar results were observed among
other pregnant rabbits gavaged daily with glyphosate technical at 175 mg/kg/day (LOAEL) during GDs
8–20 (an acute-duration oral exposure scenario); the NOAEL was 100 mg/kg/day (EPA 2017b).
Increased severity of basophilia and hypertrophy of acinar cells in parotid and submandibular salivary
glands were observed among male and female rats receiving glyphosate from the diet for 13 weeks at
410 and 421 mg/kg/day, respectively; NOAELs were 205 and 213 mg/kg/day, respectively (NTP 1992).
Increased severity of basophilia of acinar cells in parotid salivary glands were observed in male and
female mice similarly treated at estimated doses of 2,273 and 2,707 mg/kg/day, respectively; NOAELs
were 507 and 753 mg/kg/day, respectively (NTP 1992). Thus, rats appear to be much more sensitive than
mice to glyphosate treatment-related effects on salivary glands.
Among reliable animal study results, the LOAEL of 350 mg/kg/day for gastrointestinal effects (increased
incidence of soft stool and/or diarrhea) in maternal rabbits gavaged daily during GDs 6–27 represents the
most sensitive adverse effect from intermediate-duration oral exposure to glyphosate technical (EPA
1992f); the corresponding NOAEL is 175 mg/kg/day (see Table A-2). Incidence and severity data were
not available for review. Application of a NOAEL/LOAEL approach using the NOAEL of
175 mg/kg/day as the point of departure and a total uncertainty factor of 100 (10 for extrapolation from
animals to humans and 10 for human variability) would result in an intermediate-duration oral MRL of
2 mg/kg/day (rounded up from 1.75 mg/kg/day). An intermediate-duration oral MRL was not derived for
glyphosate because an intermediate-duration oral MRL of 2 mg/kg/day is higher than the acute- and
chronic-duration oral MRL of 1 mg/kg/day. Glyphosate-induced microscopic changes in salivary glands
of the rats treated orally for 13 weeks are not considered an adequate basis for MRL derivation due to
uncertainty regarding the adversity of the effect. However, application of a total uncertainty factor of
100 (10 for extrapolation from animals to humans and 10 for human variability) to the NOAEL of
205 mg/kg/day for salivary gland changes in male rats administered glyphosate in the diet for 13 weeks
would result in an intermediate-duration oral MRL of 2 mg/kg/day. The chronic-duration oral MRL of 1
mg/kg/day for glyphosate is adopted as the intermediate-duration oral MRL because 1 mg/kg/day is
considered protective of intermediate-duration oral exposure to glyphosate as well.
APPENDIX A
MRL Summary: A chronic-duration oral MRL of 1 mg/kg/day was derived for glyphosate based on
gastrointestinal effects (inflammation of gastric squamous mucosa) observed in female rats administered
glyphosate technical in the diet for up to 24 months at an estimated dose of 457 mg/kg/day; the NOAEL
was 113 mg/kg/day (EPA 1991a, 1991b). The MRL is based on a NOAEL of 113 mg/kg/day and a total
uncertainty factor of 100 (10 for animal to human extrapolation and 10 for human variability).
Selection of the Critical Effect: Several chronic-duration oral animal studies were available for
glyphosate technical (see Table A-3).
NOAEL LOAEL
Endpoint Effect (mg/kg/day) (mg/kg/day) Reference
Body weight 13% lower body weight in female M: 940 EPA 1991a, 1991b
rats at treatment week 81 F: 457 F: 1,183
No effect in rats (highest dose) M: 31.45 EPA 1992d
F: 34.02
No effect in rats (highest dose) M: 1,214 EPA 2013a
F: 1,498
11–14% lower body weight and 300 1,000 EPA 2015c
body weight gain in rats
No effect in mice (highest dose) M: 4,945 EPA 2015a
F: 6,069
No effect in mice (highest dose) 1,000 EPA 2015c
No effect in dogs (highest dose) 500 EPA 1986a, 1987
GLYPHOSATE A-13
APPENDIX A
NOAEL LOAEL
Endpoint Effect (mg/kg/day) (mg/kg/day) Reference
Gastrointestinal Inflammation of gastric squamous M: 940 EPA 1991a, 1991b
mucosa F: 113 F: 457
No effect in rats (highest dose) M: 31.45 EPA 1992d
F: 34.02
Increased severity of basophilia 100 300 EPA 2015c
and hypertrophy of acinar cells in
parotid and mandibular salivary
gland in rats
No effect in mice (highest dose) M: 4,945 EPA 2015a
F: 6,069
Hematological No effect in rats (highest dose) M: 940 EPA 1991a, 1991b
F: 1,183
No effect in rats (highest dose) M: 31.45 EPA 1992d
F: 34.02
No effect in rats (highest dose) M: 1,214 EPA 2015c
F: 1,498
No effect in rats (highest dose) 1,000 EPA 2015c
No effect in mice (highest dose) M: 4,945 EPA 2015a
F: 6,069
No effect in dogs (highest dose) 500 EPA 1986a, 1987
Hepatic No effect in rats (highest dose) M: 940 EPA 1991a, 1991b
F: 1,183
No effect in rats (highest dose) M: 31.45 EPA 1992d
F: 34.02
Increased serum AP, ALT, bilirubin M: 361 M: 1,214 EPA 2015c
in male rats; increased serum AP, F: 437 F: 1,498
ALT in female rats
No effect in rats 1,000 EPA 2015c
Centrilobular hepatocellular M: 835 M: 4,945 EPA 2015a
necrosis in male rats F: 6,069
No effect in mice (highest dose) 1,000 EPA 2015c
Renal Increased specific gravity, M: 362 M: 940 EPA 1991a, 1991b
decreased pH of urine in male rats F: 1,183
No effect in rats (highest dose) M: 31.45 EPA 1992d
F: 34.02
M: Decreased pH of urine in rats M: 361 M: 1,214 EPA 2015c
M, F: Papillary necrosis in kidney in F:437 F: 1,498
rats
Decreased pH of urine in male rats M: 300 M: 1,000 EPA 2015c
F: 1,000
Renal tubular epithelial basophilia M: 4,945 EPA 2015a
in female mice F: 968 F: 6,069
No effect in mice (highest dose) 1,000 EPA 2015c
GLYPHOSATE A-14
APPENDIX A
NOAEL LOAEL
Endpoint Effect (mg/kg/day) (mg/kg/day) Reference
Ocular Lens abnormalities in male rats M: 362 M: 940 EPA 1991a, 1991b
F: 1,183
No effect in rats M: 1,214 EPA 2015c
F: 1,498
No effect in rats 1,000 EPA 2015c
No effect in dogs (highest dose) 500 EPA 1986a, 1987
Neurological No effect in rats (highest dose) M: 1,214 EPA 2013c
F: 1,498
As shown in Table A-3, gastrointestinal endpoints are the most sensitive to chronic-duration oral
exposure of laboratory animals to glyphosate technical. Inflammation of gastric squamous mucosa was
observed in female (but not male) rats administered glyphosate technical in the diet for up to 24 months at
an estimated dose of 457 mg/kg/day; the NOAEL was 113 mg/kg/day (EPA 1991a, 1991b). Increased
severity of cytoplasmic changes in salivary gland cells (basophilia and hypertrophy of acinar cells in
parotid and submandibular salivary glands) was reported for rats receiving glyphosate from the diet for
2 years at doses ≥300 mg/kg/day (EPA 2015c). Although salivary gland cytoplasmic changes were noted
in rats at doses <300 mg/kg/day as well, the changes were reported to be only of minimal or mild
severity; therefore, they are not considered adverse effects. Furthermore, the toxicological significance of
the glyphosate treatment-related effects on salivary glands is uncertain. One chronic-duration oral study
of male and female mice found no evidence of glyphosate treatment-related gastrointestinal effects at
doses as high as 4,945 and 6,069 mg/kg/day, respectively (EPA 1985a, 1985b, 1986b, 1989, 1991c, 1993,
2015a).
EPA. 1991a. June 03, 1991. Memorandum. 40 Page(s). William Dykstra. Toxicology Branch.
Glyphosate; 2-Year combined chronic toxicity/carcinogenicity study in Sprague-Dawley rats - List A
Pesticide for Reregistration Pages 29-40 removed-registrant data. MRID 416438-01. Tox review
008390. U.S. Environmental Protection Agency.
https://archive.epa.gov/pesticides/chemicalsearch/chemical/foia/web/pdf/103601/103601-263.pdf. April
10, 2016.
EPA. 1991b. December 13, 1991. Memorandum. 38 Page(s). William Dykstra. Toxicology Branch I.
Glyphosate - EPA Registration No. 524-308 - 2-Year chronic feeding/oncogenicity study in rats with
technical glyphosate. MRID 416438-01. Tox review 008897. U.S. Environmental Protection Agency.
https://archive.epa.gov/pesticides/chemicalsearch/chemical/foia/web/pdf/103601/103601-268.pdf. April
10, 2016.
Groups of albino Sprague Dawley rats (60/sex/group) were administered technical glyphosate (96.5%
purity) in the diet at target concentrations of 0, 2,000, 8,000, or 20,000 ppm (mean measured
concentrations of 0, 1,900, 7,600, and 19,000 ppm, respectively) for up to 24 months. Rats were
monitored for survival, clinical signs, food intake, and body weight. Ten rats/sex/dose were subjected to
GLYPHOSATE A-15
APPENDIX A
There were no indications of glyphosate-related clinical signs or effects on survival. Mean body weights
of all glyphosate-treated male rats were not significantly different from that of controls. Mean body
weights and of high-dose female rats were significantly lower than that of controls at weeks 7, 13, 81, and
104 (approximately 3–4% less than that of controls); by week 81, the magnitude of the mean body weight
difference between high-dose females and their controls reached 13% (470.6 g versus 543.2 g for
controls). There were no significant differences between controls and glyphosate-treated groups
regarding food consumption. Based on mean body weight and food consumption data, estimated
glyphosate doses to controls and low-, mid-, and high-dose groups were 0, 89, 362, and 940 mg/kg/day,
respectively, for the males and 0, 113, 457, and 1,183 mg/kg/day, respectively, for the females.
Glyphosate treatment-related nonneoplastic effects included increased incidence of ocular effects (lens
abnormalities), renal effects (increased specific gravity and decreased pH of urine) in high-dose
(940 mg/kg/day) male rats, and significantly increased incidence of inflammation of gastric squamous
mucosa in female rats at 457 and 1,183 mg/kg/day (incidences of 0/59, 3/60, 9/60 [p=0.0015], and
6/59 [p=0.014] among controls, low-, mid-, and high-dose groups, respectively; statistical significance
determined using Fisher's exact test). The high-dose (1,183 mg/kg/day) group of female rats exhibited as
much as 13% lower mean body weight at treatment week 81. Relative liver weight was significantly
increased in high-dose male rats evaluated at 12 months and terminal sacrifice (13–14% greater than
controls); however, histopathologic examinations of liver sections revealed no evidence of significant
treatment-related nonneoplastic effects.
Selection of the Point of Departure: A chronic-duration oral MRL can be derived for glyphosate based
on incidences of female rats exhibiting gastric lesions in the 2-year dietary study of rats (EPA 1991a,
1991b). Incidences of female rats with gastric lesions were 0/59, 3/60, 9/60, and 6/59 for controls, low-,
mid-, and high-dose groups, respectively. All dichotomous models in the Benchmark Dose Modeling
Software (BMDS; Version 2.6) were fit to the incidence data for female rats exhibiting inflammation of
gastric squamous mucosa. A benchmark response (BMR) of 10% extra risk was applied. None of the
models produced adequate fit to the dataset, likely due to 33% lower incidence for the gastric lesion in the
high-dose group compared to the mid-dose group. Therefore, a NOAEL/LOAEL approach was employed
to derive a chronic-duration oral MRL for glyphosate. The point of departure is the NOAEL of 113
mg/kg/day for gastrointestinal lesions in the female rats of the 2-year dietary study (EPA 1991a, 1991b).
Uncertainty Factor: The NOAEL of 113 mg/kg/day was divided by a total uncertainty factor of 100:
• 10 for animal to human extrapolation
• 10 for human variability
Per ATSDR guidance, MRLs are expressed to one significant figure, making the MRL 1 mg/kg/day.
The glyphosate-induced cytoplasmic changes in salivary glands of the chronically-treated rats were not
considered for MRL derivation because the toxicological significance of the changes is uncertain.
However, consideration of the NOAEL of 113 mg/kg/day (EPA 2015c) as a point of departure,
application of a total uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for
human variability) would also result in a chronic-duration oral MRL of 1 mg/kg/day.
GLYPHOSATE A-16
APPENDIX A
A literature search and screen was conducted to identify studies examining health effects, toxicokinetics,
mechanisms of action, susceptible populations, biomarkers, chemical interactions, physical and chemical
properties, production, use, environmental fate, environmental releases, and environmental and biological
monitoring data for glyphosate. ATSDR primarily focused on peer-reviewed articles without publication
date or language restrictions. Non-peer-reviewed studies that were considered relevant to the assessment
of the health effects of glyphosate have undergone peer review by at least three ATSDR-selected experts
who have been screened for conflict of interest. The inclusion criteria used to identify relevant studies
examining the health effects of glyphosate are presented in Table B-1.
Table B-1. Inclusion Criteria for the Literature Search and Screen
Health Effects
Species
Human
Laboratory mammals
Route of exposure
Inhalation
Oral
Dermal (or ocular)
Parenteral (these studies will be considered supporting data)
Health outcome
Death
Systemic effects
Body weight effects
Respiratory effects
Cardiovascular effects
Gastrointestinal effects
Hematological effects
Musculoskeletal effects
Hepatic effects
Renal effects
Dermal effects
Ocular effects
Endocrine effects
Immunological effects
Neurological effects
Reproductive effects
Developmental effects
GLYPHOSATE B-2
APPENDIX C
Table B-1. Inclusion Criteria for the Literature Search and Screen
The following main databases were searched in February 2015 and September 2017:
• PubMed
• National Library of Medicine’s TOXLINE
• Scientific and Technical Information Network’s TOXCENTER
The search strategy used the chemical names, Chemical Abstracts Service (CAS) numbers,
synonyms, and Medical Subject Headings (MeSH) terms for glyphosate. The query strings used for
the literature search are presented in Table B-2.
The search was augmented by searching the Toxic Substances Control Act Test Submissions (TSCATS),
NTP website, and National Institute of Health Research Portfolio Online Reporting Tools Expenditures
and Results (NIH RePORTER) databases using the queries presented in Table B-3. Additional databases
GLYPHOSATE B-3
APPENDIX C
were searched in the creation of various tables and figures, such as the TRI Explorer, the Substance
Priority List (SPL) resource page, and other items as needed. Regulations applicable to glyphosate were
identified by searching international and U.S. agency websites and documents.
Review articles were identified and used for the purpose of providing background information and
identifying additional references. ATSDR also identified reports from the grey literature, which included
unpublished research reports, technical reports from government agencies, conference proceedings and
abstracts, and theses and dissertations. The reference sections of the gray literature were used as quality
assurance (QA) to ensure that no studies were missed during the literature review process. The
ToxProfiles rely on peer reviewed data such as published studies and reports from government agencies
or international organizations. In certain cases (e.g. ATSDR’s use of EPA’s DERs), ATSDR will rely on
peer reviewed studies and reports evaluating unpublished data or original studies that are not available to
ATSDR.
Database
search date Query string
PubMed ("glyphosate"[nm] OR "1071-83-6"[tw] OR "(Carboxymethylamino)methylphosphonic
9/2017 acid"[tw] OR "Carboxymethylaminomethanephosphinic acid"[tw] OR "C-K Yuyos FAV"[tw]
OR "CP 67573"[tw] OR "Folusen"[tw] OR "Forsat"[tw] OR "Glialka"[tw] OR "Glifoglex"[tw]
OR "Glifosan 747"[tw] OR "gliphosate"[tw] OR "Gliz"[tw] OR "Glyfos"[tw] OR "GlyGran"[tw]
OR "Glyphodin A"[tw] OR "Glyphomax"[tw] OR "Glyphosate"[tw] OR "Glyphosphate"[tw]
OR "Ground Bio"[tw] OR "Herbatop"[tw] OR "HM 2028"[tw] OR "Kickdown"[tw] OR "Lancer
herbicide"[tw] OR "MON 2139"[tw] OR "MON 3539"[tw] OR "MON 6000"[tw] OR "N-
(Phosphonomethyl)glycine"[tw] OR "N-(phosphonomethyl)-Glycine"[tw] OR "N-
Phosphomethylglycine"[tw] OR "N-Phosphonomethylglycine"[tw] OR "Phorsat"[tw] OR
"Phosphonomethylglycine"[tw] OR "Phosphonomethyliminoacetic acid"[tw] OR
"Pondmaster"[tw] OR "Rebel Garden"[tw] OR "Roundup Max"[tw] OR "Safal"[tw] OR
"Scout herbicide"[tw] OR "Silglif"[tw] OR "yerbimat"[tw] OR "Roundup"[tw] OR "34494-03-
6"[tw] OR "MON 0459"[tw] OR "40465-66-5"[tw] OR "MON 14420"[tw] OR "MON 8750"[tw]
OR "Roundup Hi-Load"[tw] OR "Roundup PRODry"[tw] OR "70393-85-0"[tw] OR "MON
8000"[tw] OR "Monsanto 8000"[tw] OR "Polado"[tw] OR "Trisodium hydrogen bis(N-
(phosphonatomethyl)aminoacetate"[tw] OR "39600-42-5"[tw] OR "Glyphosate
potassium"[tw] OR "Glyphosate monopotassium salt"[tw] OR "Glyphosate potassium"[tw]
OR "Glyphosate-potassium"[tw] OR "Monopotassium glyphosate"[tw] OR "Roundup
Attack"[tw] OR "Roundup Energy"[tw] OR "Roundup Maxload"[tw] OR "Roundup Original
Max"[tw] OR "Roundup Power Max"[tw] OR "Roundup Ultramax II"[tw] OR "Roundup
Weathermax"[tw] OR "Touchdown Forte HiTech"[tw] OR "Transorb R"[tw] OR
"Weathermax"[tw] OR "Zapp Qi"[tw] OR "70901-12-1"[tw] OR "Glyphosate-potassium"[tw]
OR "Potassium glyphosate"[tw] OR "Potassium N-(phosphonomethyl)glycine"[tw] OR
"Uragan Forte"[tw] OR "VisionMAX"[tw] OR "N-(phosphonomethyl)glycine potassium
salt"[tw] OR "114370-14-8"[tw] OR "Glyphosate ammonium"[tw] OR "N-
(phosphonomethyl)glycine ammonium salt"[tw] OR "69254-40-6"[tw] OR "Glyphosate-
diammonium"[tw] OR "Diammonium N-(phosphonomethyl)glycine"[tw] OR "N-
(phosphonomethyl)glycine diammonium salt"[tw]) AND (cancer[sb] OR "neoplasms"[mh]
OR "carcinogenicity tests"[mh] OR "carcinogens"[mh] OR "cell division/drug effects"[mh]
OR "cell cycle/drug effects"[mh] OR "cell line, tumor/drug effects"[mh] OR "gene
expression regulation, neoplastic"[mh] OR "neoplasm proteins/drug effects"[mh] OR
"angiogenesis inducing agents"[mh] OR "myelodysplastic-myeloproliferative diseases"[mh]
OR cancer*[tw] OR carcinog*[tw] OR carcinom*[tw] OR cocarcinog*[tw] OR lymphoma*[tw]
OR neoplas*[tw] OR oncogen*[tw] OR precancer*[tw] OR tumor*[tw] OR tumour*[tw]) AND
GLYPHOSATE B-4
APPENDIX C
Database
search date Query string
(2014/02/01 : 3000[dp] OR 2015/02/01 : 3000[mhda] OR 2015/02/01 : 3000[crdat] OR
2015/02/01 : 3000[edat])
("glyphosate, isopropyl amine salt"[nm] OR "N-(phosphonomethyl)glycine
trimethylsulfonium salt"[nm] OR "38641-94-0"[tw] OR "Glyphosate-
isopropylammonium"[tw] OR "Glyphosate isopropylamine salt"[tw] OR "Azural AT"[tw] OR
"CP 70139"[tw] OR "Fosulen"[tw] OR "Glifosato estrella"[tw] OR "Glycel"[tw] OR "Glycine,
N-(phosphonomethyl)-, cmpd with 2-propanamine (1:1)"[tw] OR "Glyfos AU"[tw] OR
"Glyfos BIO"[tw] OR "Glyphosate isopropylamine salt"[tw] OR "Glyphosate
mono(isopropylamine) salt"[tw] OR "Glyphosate-isopropylammonium"[tw] OR "Glyphosate-
mono(isopropylammonium)"[tw] OR "Landmaster"[tw] OR "MON 139"[tw] OR "MON
39"[tw] OR "N-(Phosphonomethyl)glycine isopropylamine salt"[tw] OR "N-
(Phosphonomethyl)glycine isopropylammonium salt"[tw] OR "N-(Phosphonomethyl)glycine
monoisopropylamine salt"[tw] OR "Nitosorg"[tw] OR "Ron-do"[tw] OR "Utal"[tw] OR "Utal
(herbicide)"[tw] OR "Vision (herbicide)"[tw] OR "2-Propanamine, compd, with N-
(phosphonomethyl)glycine (1:1)"[tw] OR "Glycine, N-(phosphonomethyl)-, compd. with 2-
propanamine (1:1)"[tw] OR "N-(Phosphonomethyl)glycine, compound with 2-propylamine
(1:1)"[tw] OR "Isopropylamine glyphosate"[tw] OR "81591-81-3"[tw] OR "Glyphosate-
trimesium"[tw] OR "Glyphosphate-trimesium"[tw] OR "Avans 330"[tw] OR "Glyphosate
mono(trimethylsulfonium) salt"[tw] OR "Glyphosate trimethylsulfonium salt"[tw] OR
"Glyphosate-trimesium"[tw] OR "Medallon"[tw] OR "Ouragan"[tw] OR "R 50224"[tw] OR
"SC 0224"[tw] OR "Sulfosate"[tw] OR "Sulphosate"[tw] OR "Touchdown herbicide"[tw] OR
"Trimethylsulfonium carboxymethylamino-methylphosphonate"[tw] OR "Trimethylsulfonium
glyphosate"[tw] OR "Glycine, N-(phosphonomethyl)-, ion(1-), trimethylsulfonium"[tw] OR
"Sulfosate"[tw]) AND (cancer[sb] OR "neoplasms"[mh] OR "carcinogenicity tests"[mh] OR
"carcinogens"[mh] OR "cell division/drug effects"[mh] OR "cell cycle/drug effects"[mh] OR
"cell line, tumor/drug effects"[mh] OR "gene expression regulation, neoplastic"[mh] OR
"neoplasm proteins/drug effects"[mh] OR "angiogenesis inducing agents"[mh] OR
"myelodysplastic-myeloproliferative diseases"[mh] OR cancer*[tw] OR carcinog*[tw] OR
carcinom*[tw] OR cocarcinog*[tw] OR lymphoma*[tw] OR neoplas*[tw] OR oncogen*[tw]
OR precancer*[tw] OR tumor*[tw] OR tumour*[tw]) AND (2014/02/01 : 3000[dp] OR
2015/02/01 : 3000[mhda] OR 2015/02/01 : 3000[crdat] OR 2015/02/01 : 3000[edat])
2/2015 ("glyphosate"[nm]) OR (("1071-83-6"[tw] OR "(Carboxymethylamino)methylphosphonic
acid"[tw] OR "Carboxymethylaminomethanephosphinic acid"[tw] OR "C-K Yuyos FAV"[tw]
OR "CP 67573"[tw] OR "Folusen"[tw] OR "Forsat"[tw] OR "Glialka"[tw] OR "Glifoglex"[tw]
OR "Glifosan 747"[tw] OR "gliphosate"[tw] OR "Gliz"[tw] OR "Glyfos"[tw] OR "GlyGran"[tw]
OR "Glyphodin A"[tw] OR "Glyphomax"[tw] OR "Glyphosate"[tw] OR "Glyphosphate"[tw]
OR "Ground Bio"[tw] OR "Herbatop"[tw] OR "HM 2028"[tw] OR "Kickdown"[tw] OR "Lancer
herbicide"[tw] OR "MON 2139"[tw] OR "MON 3539"[tw] OR "MON 6000"[tw] OR "N-
(Phosphonomethyl)glycine"[tw] OR "N-(phosphonomethyl)-Glycine"[tw] OR "N-
Phosphomethylglycine"[tw] OR "N-Phosphonomethylglycine"[tw] OR "Phorsat"[tw] OR
"Phosphonomethylglycine"[tw] OR "Phosphonomethyliminoacetic acid"[tw] OR
"Pondmaster"[tw] OR "Rebel Garden"[tw] OR "Roundup Max"[tw] OR "Safal"[tw] OR
"Scout herbicide"[tw] OR "Silglif"[tw] OR "yerbimat"[tw]) AND (to[sh] OR po[sh] OR ae[sh]
OR pk[sh] OR (me[sh] AND ("humans"[mh] OR "animals"[mh])) OR ci[sh] OR bl[sh] OR
cf[sh] OR ur[sh] OR "environmental exposure"[mh] OR "endocrine system"[mh] OR
"hormones, hormone substitutes, and hormone antagonists"[mh] OR "endocrine
disruptors"[mh] OR (("Computational biology"[mh] OR "Medical Informatics"[mh] OR
Genomics[mh] OR Genome[mh] OR Proteomics[mh] OR Proteome[mh] OR
Metabolomics[mh] OR Metabolome[mh] OR Genes[mh] OR "Gene expression"[mh] OR
Phenotype[mh] OR genetics[mh] OR genotype[mh] OR Transcriptome[mh] OR ("Systems
GLYPHOSATE B-5
APPENDIX C
Database
search date Query string
Biology"[mh] AND ("Environmental Exposure"[mh] OR "Epidemiological Monitoring"[mh]
OR analysis[sh])) OR "Transcription, Genetic "[mh] OR "Reverse transcription"[mh] OR
"Transcriptional activation"[mh] OR "Transcription factors"[mh] OR ("biosynthesis"[sh] AND
(RNA[mh] OR DNA[mh])) OR "RNA, Messenger"[mh] OR "RNA, Transfer"[mh] OR
"peptide biosynthesis"[mh] OR "protein biosynthesis"[mh] OR "Reverse Transcriptase
Polymerase Chain Reaction"[mh] OR "Base Sequence"[mh] OR "Trans-activators"[mh] OR
"Gene Expression Profiling"[mh])) OR cancer[sb] OR "pharmacology"[Majr])) OR (("1071-
83-6"[tw] OR "(Carboxymethylamino)methylphosphonic acid"[tw] OR
"Carboxymethylaminomethanephosphinic acid"[tw] OR "C-K Yuyos FAV"[tw] OR "CP
67573"[tw] OR "Folusen"[tw] OR "Forsat"[tw] OR "Glialka"[tw] OR "Glifoglex"[tw] OR
"Glifosan 747"[tw] OR "gliphosate"[tw] OR "Gliz"[tw] OR "Glyfos"[tw] OR "GlyGran"[tw] OR
"Glyphodin A"[tw] OR "Glyphomax"[tw] OR "Glyphosate"[tw] OR "Glyphosphate"[tw] OR
"Ground Bio"[tw] OR "Herbatop"[tw] OR "HM 2028"[tw] OR "Kickdown"[tw] OR "Lancer
herbicide"[tw] OR "MON 2139"[tw] OR "MON 3539"[tw] OR "MON 6000"[tw] OR "N-
(Phosphonomethyl)glycine"[tw] OR "N-(phosphonomethyl)-Glycine"[tw] OR "N-
Phosphomethylglycine"[tw] OR "N-Phosphonomethylglycine"[tw] OR "Phorsat"[tw] OR
"Phosphonomethylglycine"[tw] OR "Phosphonomethyliminoacetic acid"[tw] OR
"Pondmaster"[tw] OR "Rebel Garden"[tw] OR "Roundup Max"[tw] OR "Safal"[tw] OR
"Scout herbicide"[tw] OR "Silglif"[tw] OR "yerbimat"[tw]) NOT medline[sb])
("Roundup"[tw] AND (monsanto[tw] OR "antifungal agents"[Pharmacological Action] OR
"antifungal agents"[MeSH Terms] OR "antifungal"[tw] OR "anti-fungal"[tw] OR "enzyme
inhibitors"[Pharmacological Action] OR "enzyme inhibitors"[MeSH Terms] OR
("enzyme"[tw] AND inhibitor*[tw]) OR "enzyme inhibitors"[tw] OR "enzyme inhibitor"[tw] OR
"herbicides"[Pharmacological Action] OR "herbicides"[MeSH Terms] OR "herbicides"[tw]
OR "herbicide"[tw] OR "uncoupling agents"[Pharmacological Action] OR "uncoupling
agents"[MeSH Terms] OR ("uncoupling"[tw] AND agent*[tw]) OR "uncoupling agent"[tw]
OR "uncoupling agents"[tw] OR "pesticides"[mh] OR pesticide*[tw])) NOT
(("glyphosate"[nm]) OR (("1071-83-6"[tw] OR "(Carboxymethylamino)methylphosphonic
acid"[tw] OR "Carboxymethylaminomethanephosphinic acid"[tw] OR "C-K Yuyos FAV"[tw]
OR "CP 67573"[tw] OR "Folusen"[tw] OR "Forsat"[tw] OR "Glialka"[tw] OR "Glifoglex"[tw]
OR "Glifosan 747"[tw] OR "gliphosate"[tw] OR "Gliz"[tw] OR "Glyfos"[tw] OR "GlyGran"[tw]
OR "Glyphodin A"[tw] OR "Glyphomax"[tw] OR "Glyphosate"[tw] OR "Glyphosphate"[tw]
OR "Ground Bio"[tw] OR "Herbatop"[tw] OR "HM 2028"[tw] OR "Kickdown"[tw] OR "Lancer
herbicide"[tw] OR "MON 2139"[tw] OR "MON 3539"[tw] OR "MON 6000"[tw] OR "N-
(Phosphonomethyl)glycine"[tw] OR "N-(phosphonomethyl)-Glycine"[tw] OR "N-
Phosphomethylglycine"[tw] OR "N-Phosphonomethylglycine"[tw] OR "Phorsat"[tw] OR
"Phosphonomethylglycine"[tw] OR "Phosphonomethyliminoacetic acid"[tw] OR
"Pondmaster"[tw] OR "Rebel Garden"[tw] OR "Roundup Max"[tw] OR "Safal"[tw] OR
"Scout herbicide"[tw] OR "Silglif"[tw] OR "yerbimat"[tw]) AND (to[sh] OR po[sh] OR ae[sh]
OR pk[sh] OR (me[sh] AND ("humans"[mh] OR "animals"[mh])) OR ci[sh] OR bl[sh] OR
cf[sh] OR ur[sh] OR "environmental exposure"[mh] OR "endocrine system"[mh] OR
"hormones, hormone substitutes, and hormone antagonists"[mh] OR "endocrine
disruptors"[mh] OR (("Computational biology"[mh] OR "Medical Informatics"[mh] OR
Genomics[mh] OR Genome[mh] OR Proteomics[mh] OR Proteome[mh] OR
Metabolomics[mh] OR Metabolome[mh] OR Genes[mh] OR "Gene expression"[mh] OR
Phenotype[mh] OR genetics[mh] OR genotype[mh] OR Transcriptome[mh] OR ("Systems
Biology"[mh] AND ("Environmental Exposure"[mh] OR "Epidemiological Monitoring"[mh]
OR analysis[sh])) OR "Transcription, Genetic "[mh] OR "Reverse transcription"[mh] OR
"Transcriptional activation"[mh] OR "Transcription factors"[mh] OR ("biosynthesis"[sh] AND
(RNA[mh] OR DNA[mh])) OR "RNA, Messenger"[mh] OR "RNA, Transfer"[mh] OR
GLYPHOSATE B-6
APPENDIX C
Database
search date Query string
"peptide biosynthesis"[mh] OR "protein biosynthesis"[mh] OR "Reverse Transcriptase
Polymerase Chain Reaction"[mh] OR "Base Sequence"[mh] OR "Trans-activators"[mh] OR
"Gene Expression Profiling"[mh])) OR cancer[sb] OR "pharmacology"[Majr])) OR (("1071-
83-6"[tw] OR "(Carboxymethylamino)methylphosphonic acid"[tw] OR
"Carboxymethylaminomethanephosphinic acid"[tw] OR "C-K Yuyos FAV"[tw] OR "CP
67573"[tw] OR "Folusen"[tw] OR "Forsat"[tw] OR "Glialka"[tw] OR "Glifoglex"[tw] OR
"Glifosan 747"[tw] OR "gliphosate"[tw] OR "Gliz"[tw] OR "Glyfos"[tw] OR "GlyGran"[tw] OR
"Glyphodin A"[tw] OR "Glyphomax"[tw] OR "Glyphosate"[tw] OR "Glyphosphate"[tw] OR
"Ground Bio"[tw] OR "Herbatop"[tw] OR "HM 2028"[tw] OR "Kickdown"[tw] OR "Lancer
herbicide"[tw] OR "MON 2139"[tw] OR "MON 3539"[tw] OR "MON 6000"[tw] OR "N-
(Phosphonomethyl)glycine"[tw] OR "N-(phosphonomethyl)-Glycine"[tw] OR "N-
Phosphomethylglycine"[tw] OR "N-Phosphonomethylglycine"[tw] OR "Phorsat"[tw] OR
"Phosphonomethylglycine"[tw] OR "Phosphonomethyliminoacetic acid"[tw] OR
"Pondmaster"[tw] OR "Rebel Garden"[tw] OR "Roundup Max"[tw] OR "Safal"[tw] OR
"Scout herbicide"[tw] OR "Silglif"[tw] OR "yerbimat"[tw]) NOT medline[sb]))
("34494-03-6"[tw] OR "MON 0459"[tw] OR "40465-66-5"[tw] OR "MON 14420"[tw] OR
"MON 8750"[tw] OR "Roundup Hi-Load"[tw] OR "Roundup PRODry"[tw] OR "70393-85-
0"[tw] OR "MON 8000"[tw] OR "Monsanto 8000"[tw] OR "Polado"[tw] OR "Trisodium
hydrogen bis(N-(phosphonatomethyl)aminoacetate"[tw]) AND (to[sh] OR po[sh] OR ae[sh]
OR pk[sh] OR (me[sh] AND ("humans"[mh] OR "animals"[mh])) OR ci[sh] OR bl[sh] OR
cf[sh] OR ur[sh] OR "environmental exposure"[mh] OR "endocrine system"[mh] OR
"hormones, hormone substitutes, and hormone antagonists"[mh] OR "endocrine
disruptors"[mh] OR (("Computational biology"[mh] OR "Medical Informatics"[mh] OR
Genomics[mh] OR Genome[mh] OR Proteomics[mh] OR Proteome[mh] OR
Metabolomics[mh] OR Metabolome[mh] OR Genes[mh] OR "Gene expression"[mh] OR
Phenotype[mh] OR genetics[mh] OR genotype[mh] OR Transcriptome[mh] OR ("Systems
Biology"[mh] AND ("Environmental Exposure"[mh] OR "Epidemiological Monitoring"[mh]
OR analysis[sh])) OR "Transcription, Genetic "[mh] OR "Reverse transcription"[mh] OR
"Transcriptional activation"[mh] OR "Transcription factors"[mh] OR ("biosynthesis"[sh] AND
(RNA[mh] OR DNA[mh])) OR "RNA, Messenger"[mh] OR "RNA, Transfer"[mh] OR
"peptide biosynthesis"[mh] OR "protein biosynthesis"[mh] OR "Reverse Transcriptase
Polymerase Chain Reaction"[mh] OR "Base Sequence"[mh] OR "Trans-activators"[mh] OR
"Gene Expression Profiling"[mh])) OR cancer[sb] OR "pharmacology"[Majr])
("39600-42-5"[tw] OR "Glyphosate potassium"[tw] OR "Glyphosate monopotassium
salt"[tw] OR "Glyphosate potassium"[tw] OR "Glyphosate-potassium"[tw] OR
"Monopotassium glyphosate"[tw] OR "Roundup Attack"[tw] OR "Roundup Energy"[tw] OR
"Roundup Maxload"[tw] OR "Roundup Original Max"[tw] OR "Roundup Power Max"[tw] OR
"Roundup Ultramax II"[tw] OR "Roundup Weathermax"[tw] OR "Touchdown Forte
HiTech"[tw] OR "Transorb R"[tw] OR "Weathermax"[tw] OR "Zapp Qi"[tw] OR "70901-12-
1"[tw] OR "Glyphosate-potassium"[tw] OR "Potassium glyphosate"[tw] OR "Potassium N-
(phosphonomethyl)glycine"[tw] OR "Uragan Forte"[tw] OR "VisionMAX"[tw] OR "N-
(phosphonomethyl)glycine potassium salt"[tw] OR "114370-14-8"[tw] OR "Glyphosate
ammonium"[tw] OR "N-(phosphonomethyl)glycine ammonium salt"[tw] OR "69254-40-
6"[tw] OR "Glyphosate-diammonium"[tw] OR "Diammonium N-
(phosphonomethyl)glycine"[tw] OR "N-(phosphonomethyl)glycine diammonium salt"[tw])
NOT (("glyphosate"[nm]) OR (("1071-83-6"[tw] OR
"(Carboxymethylamino)methylphosphonic acid"[tw] OR
"Carboxymethylaminomethanephosphinic acid"[tw] OR "C-K Yuyos FAV"[tw] OR "CP
67573"[tw] OR "Folusen"[tw] OR "Forsat"[tw] OR "Glialka"[tw] OR "Glifoglex"[tw] OR
"Glifosan 747"[tw] OR "gliphosate"[tw] OR "Gliz"[tw] OR "Glyfos"[tw] OR "GlyGran"[tw] OR
GLYPHOSATE B-7
APPENDIX C
Database
search date Query string
"Glyphodin A"[tw] OR "Glyphomax"[tw] OR "Glyphosate"[tw] OR "Glyphosphate"[tw] OR
"Ground Bio"[tw] OR "Herbatop"[tw] OR "HM 2028"[tw] OR "Kickdown"[tw] OR "Lancer
herbicide"[tw] OR "MON 2139"[tw] OR "MON 3539"[tw] OR "MON 6000"[tw] OR "N-
(Phosphonomethyl)glycine"[tw] OR "N-(phosphonomethyl)-Glycine"[tw] OR "N-
Phosphomethylglycine"[tw] OR "N-Phosphonomethylglycine"[tw] OR "Phorsat"[tw] OR
"Phosphonomethylglycine"[tw] OR "Phosphonomethyliminoacetic acid"[tw] OR
"Pondmaster"[tw] OR "Rebel Garden"[tw] OR "Roundup Max"[tw] OR "Safal"[tw] OR
"Scout herbicide"[tw] OR "Silglif"[tw] OR "yerbimat"[tw]) AND (to[sh] OR po[sh] OR ae[sh]
OR pk[sh] OR (me[sh] AND ("humans"[mh] OR "animals"[mh])) OR ci[sh] OR bl[sh] OR
cf[sh] OR ur[sh] OR "environmental exposure"[mh] OR "endocrine system"[mh] OR
"hormones, hormone substitutes, and hormone antagonists"[mh] OR "endocrine
disruptors"[mh] OR (("Computational biology"[mh] OR "Medical Informatics"[mh] OR
Genomics[mh] OR Genome[mh] OR Proteomics[mh] OR Proteome[mh] OR
Metabolomics[mh] OR Metabolome[mh] OR Genes[mh] OR "Gene expression"[mh] OR
Phenotype[mh] OR genetics[mh] OR genotype[mh] OR Transcriptome[mh] OR ("Systems
Biology"[mh] AND ("Environmental Exposure"[mh] OR "Epidemiological Monitoring"[mh]
OR analysis[sh])) OR "Transcription, Genetic "[mh] OR "Reverse transcription"[mh] OR
"Transcriptional activation"[mh] OR "Transcription factors"[mh] OR ("biosynthesis"[sh] AND
(RNA[mh] OR DNA[mh])) OR "RNA, Messenger"[mh] OR "RNA, Transfer"[mh] OR
"peptide biosynthesis"[mh] OR "protein biosynthesis"[mh] OR "Reverse Transcriptase
Polymerase Chain Reaction"[mh] OR "Base Sequence"[mh] OR "Trans-activators"[mh] OR
"Gene Expression Profiling"[mh])) OR cancer[sb] OR "pharmacology"[Majr])) OR (("1071-
83-6"[tw] OR "(Carboxymethylamino)methylphosphonic acid"[tw] OR
"Carboxymethylaminomethanephosphinic acid"[tw] OR "C-K Yuyos FAV"[tw] OR "CP
67573"[tw] OR "Folusen"[tw] OR "Forsat"[tw] OR "Glialka"[tw] OR "Glifoglex"[tw] OR
"Glifosan 747"[tw] OR "gliphosate"[tw] OR "Gliz"[tw] OR "Glyfos"[tw] OR "GlyGran"[tw] OR
"Glyphodin A"[tw] OR "Glyphomax"[tw] OR "Glyphosate"[tw] OR "Glyphosphate"[tw] OR
"Ground Bio"[tw] OR "Herbatop"[tw] OR "HM 2028"[tw] OR "Kickdown"[tw] OR "Lancer
herbicide"[tw] OR "MON 2139"[tw] OR "MON 3539"[tw] OR "MON 6000"[tw] OR "N-
(Phosphonomethyl)glycine"[tw] OR "N-(phosphonomethyl)-Glycine"[tw] OR "N-
Phosphomethylglycine"[tw] OR "N-Phosphonomethylglycine"[tw] OR "Phorsat"[tw] OR
"Phosphonomethylglycine"[tw] OR "Phosphonomethyliminoacetic acid"[tw] OR
"Pondmaster"[tw] OR "Rebel Garden"[tw] OR "Roundup Max"[tw] OR "Safal"[tw] OR
"Scout herbicide"[tw] OR "Silglif"[tw] OR "yerbimat"[tw]) NOT medline[sb]) OR
("Roundup"[tw] AND (monsanto[tw] OR "antifungal agents"[Pharmacological Action] OR
"antifungal agents"[MeSH Terms] OR "antifungal"[tw] OR "anti-fungal"[tw] OR "enzyme
inhibitors"[Pharmacological Action] OR "enzyme inhibitors"[MeSH Terms] OR
("enzyme"[tw] AND inhibitor*[tw]) OR "enzyme inhibitors"[tw] OR "enzyme inhibitor"[tw] OR
"herbicides"[Pharmacological Action] OR "herbicides"[MeSH Terms] OR "herbicides"[tw]
OR "herbicide"[tw] OR "uncoupling agents"[Pharmacological Action] OR "uncoupling
agents"[MeSH Terms] OR ("uncoupling"[tw] AND agent*[tw]) OR "uncoupling agent"[tw]
OR "uncoupling agents"[tw] OR "pesticides"[mh] OR pesticide*[tw])))
((("glyphosate, isopropyl amine salt"[nm]) OR ("N-(phosphonomethyl)glycine
trimethylsulfonium salt"[nm])) NOT (("glyphosate"[nm]) OR (("1071-83-6"[tw] OR
"(Carboxymethylamino)methylphosphonic acid"[tw] OR
"Carboxymethylaminomethanephosphinic acid"[tw] OR "C-K Yuyos FAV"[tw] OR "CP
67573"[tw] OR "Folusen"[tw] OR "Forsat"[tw] OR "Glialka"[tw] OR "Glifoglex"[tw] OR
"Glifosan 747"[tw] OR "gliphosate"[tw] OR "Gliz"[tw] OR "Glyfos"[tw] OR "GlyGran"[tw] OR
"Glyphodin A"[tw] OR "Glyphomax"[tw] OR "Glyphosate"[tw] OR "Glyphosphate"[tw] OR
"Ground Bio"[tw] OR "Herbatop"[tw] OR "HM 2028"[tw] OR "Kickdown"[tw] OR "Lancer
GLYPHOSATE B-8
APPENDIX C
Database
search date Query string
herbicide"[tw] OR "MON 2139"[tw] OR "MON 3539"[tw] OR "MON 6000"[tw] OR "N-
(Phosphonomethyl)glycine"[tw] OR "N-(phosphonomethyl)-Glycine"[tw] OR "N-
Phosphomethylglycine"[tw] OR "N-Phosphonomethylglycine"[tw] OR "Phorsat"[tw] OR
"Phosphonomethylglycine"[tw] OR "Phosphonomethyliminoacetic acid"[tw] OR
"Pondmaster"[tw] OR "Rebel Garden"[tw] OR "Roundup Max"[tw] OR "Safal"[tw] OR
"Scout herbicide"[tw] OR "Silglif"[tw] OR "yerbimat"[tw]) AND (to[sh] OR po[sh] OR ae[sh]
OR pk[sh] OR (me[sh] AND ("humans"[mh] OR "animals"[mh])) OR ci[sh] OR bl[sh] OR
cf[sh] OR ur[sh] OR "environmental exposure"[mh] OR "endocrine system"[mh] OR
"hormones, hormone substitutes, and hormone antagonists"[mh] OR "endocrine
disruptors"[mh] OR (("Computational biology"[mh] OR "Medical Informatics"[mh] OR
Genomics[mh] OR Genome[mh] OR Proteomics[mh] OR Proteome[mh] OR
Metabolomics[mh] OR Metabolome[mh] OR Genes[mh] OR "Gene expression"[mh] OR
Phenotype[mh] OR genetics[mh] OR genotype[mh] OR Transcriptome[mh] OR ("Systems
Biology"[mh] AND ("Environmental Exposure"[mh] OR "Epidemiological Monitoring"[mh]
OR analysis[sh])) OR "Transcription, Genetic "[mh] OR "Reverse transcription"[mh] OR
"Transcriptional activation"[mh] OR "Transcription factors"[mh] OR ("biosynthesis"[sh] AND
(RNA[mh] OR DNA[mh])) OR "RNA, Messenger"[mh] OR "RNA, Transfer"[mh] OR
"peptide biosynthesis"[mh] OR "protein biosynthesis"[mh] OR "Reverse Transcriptase
Polymerase Chain Reaction"[mh] OR "Base Sequence"[mh] OR "Trans-activators"[mh] OR
"Gene Expression Profiling"[mh])) OR cancer[sb] OR "pharmacology"[Majr])) OR (("1071-
83-6"[tw] OR "(Carboxymethylamino)methylphosphonic acid"[tw] OR
"Carboxymethylaminomethanephosphinic acid"[tw] OR "C-K Yuyos FAV"[tw] OR "CP
67573"[tw] OR "Folusen"[tw] OR "Forsat"[tw] OR "Glialka"[tw] OR "Glifoglex"[tw] OR
"Glifosan 747"[tw] OR "gliphosate"[tw] OR "Gliz"[tw] OR "Glyfos"[tw] OR "GlyGran"[tw] OR
"Glyphodin A"[tw] OR "Glyphomax"[tw] OR "Glyphosate"[tw] OR "Glyphosphate"[tw] OR
"Ground Bio"[tw] OR "Herbatop"[tw] OR "HM 2028"[tw] OR "Kickdown"[tw] OR "Lancer
herbicide"[tw] OR "MON 2139"[tw] OR "MON 3539"[tw] OR "MON 6000"[tw] OR "N-
(Phosphonomethyl)glycine"[tw] OR "N-(phosphonomethyl)-Glycine"[tw] OR "N-
Phosphomethylglycine"[tw] OR "N-Phosphonomethylglycine"[tw] OR "Phorsat"[tw] OR
"Phosphonomethylglycine"[tw] OR "Phosphonomethyliminoacetic acid"[tw] OR
"Pondmaster"[tw] OR "Rebel Garden"[tw] OR "Roundup Max"[tw] OR "Safal"[tw] OR
"Scout herbicide"[tw] OR "Silglif"[tw] OR "yerbimat"[tw]) NOT medline[sb]) OR
("Roundup"[tw] AND (monsanto[tw] OR "antifungal agents"[Pharmacological Action] OR
"antifungal agents"[MeSH Terms] OR "antifungal"[tw] OR "anti-fungal"[tw] OR "enzyme
inhibitors"[Pharmacological Action] OR "enzyme inhibitors"[MeSH Terms] OR
("enzyme"[tw] AND inhibitor*[tw]) OR "enzyme inhibitors"[tw] OR "enzyme inhibitor"[tw] OR
"herbicides"[Pharmacological Action] OR "herbicides"[MeSH Terms] OR "herbicides"[tw]
OR "herbicide"[tw] OR "uncoupling agents"[Pharmacological Action] OR "uncoupling
agents"[MeSH Terms] OR ("uncoupling"[tw] AND agent*[tw]) OR "uncoupling agent"[tw]
OR "uncoupling agents"[tw] OR "pesticides"[mh] OR pesticide*[tw])))) OR (("38641-94-
0"[tw] OR "Glyphosate-isopropylammonium"[tw] OR "Glyphosate isopropylamine salt"[tw]
OR "Azural AT"[tw] OR "CP 70139"[tw] OR "Fosulen"[tw] OR "Glifosato estrella"[tw] OR
"Glycel"[tw] OR "Glycine, N-(phosphonomethyl)-, cmpd with 2-propanamine (1:1)"[tw] OR
"Glyfos AU"[tw] OR "Glyfos BIO"[tw] OR "Glyphosate isopropylamine salt"[tw] OR
"Glyphosate mono(isopropylamine) salt"[tw] OR "Glyphosate-isopropylammonium"[tw] OR
"Glyphosate-mono(isopropylammonium)"[tw] OR "Landmaster"[tw] OR "MON 139"[tw] OR
"MON 39"[tw] OR "N-(Phosphonomethyl)glycine isopropylamine salt"[tw] OR "N-
(Phosphonomethyl)glycine isopropylammonium salt"[tw] OR "N-(Phosphonomethyl)glycine
monoisopropylamine salt"[tw] OR "Nitosorg"[tw] OR "Ron-do"[tw] OR "Utal"[tw] OR "Utal
(herbicide)"[tw] OR "Vision (herbicide)"[tw] OR "2-Propanamine, compd, with N-
GLYPHOSATE B-9
APPENDIX C
Database
search date Query string
(phosphonomethyl)glycine (1:1)"[tw] OR "Glycine, N-(phosphonomethyl)-, compd. with 2-
propanamine (1:1)"[tw] OR "N-(Phosphonomethyl)glycine, compound with 2-propylamine
(1:1)"[tw] OR "Isopropylamine glyphosate"[tw] OR "81591-81-3"[tw] OR "Glyphosate-
trimesium"[tw] OR "Glyphosphate-trimesium"[tw] OR "Avans 330"[tw] OR "Glyphosate
mono(trimethylsulfonium) salt"[tw] OR "Glyphosate trimethylsulfonium salt"[tw] OR
"Glyphosate-trimesium"[tw] OR "Medallon"[tw] OR "Ouragan"[tw] OR "R 50224"[tw] OR
"SC 0224"[tw] OR "Sulfosate"[tw] OR "Sulphosate"[tw] OR "Touchdown herbicide"[tw] OR
"Trimethylsulfonium carboxymethylamino-methylphosphonate"[tw] OR "Trimethylsulfonium
glyphosate"[tw] OR "Glycine, N-(phosphonomethyl)-, ion(1-), trimethylsulfonium"[tw] OR
"Sulfosate"[tw]) NOT (("glyphosate"[nm]) OR (("1071-83-6"[tw] OR
"(Carboxymethylamino)methylphosphonic acid"[tw] OR
"Carboxymethylaminomethanephosphinic acid"[tw] OR "C-K Yuyos FAV"[tw] OR "CP
67573"[tw] OR "Folusen"[tw] OR "Forsat"[tw] OR "Glialka"[tw] OR "Glifoglex"[tw] OR
"Glifosan 747"[tw] OR "gliphosate"[tw] OR "Gliz"[tw] OR "Glyfos"[tw] OR "GlyGran"[tw] OR
"Glyphodin A"[tw] OR "Glyphomax"[tw] OR "Glyphosate"[tw] OR "Glyphosphate"[tw] OR
"Ground Bio"[tw] OR "Herbatop"[tw] OR "HM 2028"[tw] OR "Kickdown"[tw] OR "Lancer
herbicide"[tw] OR "MON 2139"[tw] OR "MON 3539"[tw] OR "MON 6000"[tw] OR "N-
(Phosphonomethyl)glycine"[tw] OR "N-(phosphonomethyl)-Glycine"[tw] OR "N-
Phosphomethylglycine"[tw] OR "N-Phosphonomethylglycine"[tw] OR "Phorsat"[tw] OR
"Phosphonomethylglycine"[tw] OR "Phosphonomethyliminoacetic acid"[tw] OR
"Pondmaster"[tw] OR "Rebel Garden"[tw] OR "Roundup Max"[tw] OR "Safal"[tw] OR
"Scout herbicide"[tw] OR "Silglif"[tw] OR "yerbimat"[tw]) AND (to[sh] OR po[sh] OR ae[sh]
OR pk[sh] OR (me[sh] AND ("humans"[mh] OR "animals"[mh])) OR ci[sh] OR bl[sh] OR
cf[sh] OR ur[sh] OR "environmental exposure"[mh] OR "endocrine system"[mh] OR
"hormones, hormone substitutes, and hormone antagonists"[mh] OR "endocrine
disruptors"[mh] OR (("Computational biology"[mh] OR "Medical Informatics"[mh] OR
Genomics[mh] OR Genome[mh] OR Proteomics[mh] OR Proteome[mh] OR
Metabolomics[mh] OR Metabolome[mh] OR Genes[mh] OR "Gene expression"[mh] OR
Phenotype[mh] OR genetics[mh] OR genotype[mh] OR Transcriptome[mh] OR ("Systems
Biology"[mh] AND ("Environmental Exposure"[mh] OR "Epidemiological Monitoring"[mh]
OR analysis[sh])) OR "Transcription, Genetic "[mh] OR "Reverse transcription"[mh] OR
"Transcriptional activation"[mh] OR "Transcription factors"[mh] OR ("biosynthesis"[sh] AND
(RNA[mh] OR DNA[mh])) OR "RNA, Messenger"[mh] OR "RNA, Transfer"[mh] OR
"peptide biosynthesis"[mh] OR "protein biosynthesis"[mh] OR "Reverse Transcriptase
Polymerase Chain Reaction"[mh] OR "Base Sequence"[mh] OR "Trans-activators"[mh] OR
"Gene Expression Profiling"[mh])) OR cancer[sb] OR "pharmacology"[Majr])) OR (("1071-
83-6"[tw] OR "(Carboxymethylamino)methylphosphonic acid"[tw] OR
"Carboxymethylaminomethanephosphinic acid"[tw] OR "C-K Yuyos FAV"[tw] OR "CP
67573"[tw] OR "Folusen"[tw] OR "Forsat"[tw] OR "Glialka"[tw] OR "Glifoglex"[tw] OR
"Glifosan 747"[tw] OR "gliphosate"[tw] OR "Gliz"[tw] OR "Glyfos"[tw] OR "GlyGran"[tw] OR
"Glyphodin A"[tw] OR "Glyphomax"[tw] OR "Glyphosate"[tw] OR "Glyphosphate"[tw] OR
"Ground Bio"[tw] OR "Herbatop"[tw] OR "HM 2028"[tw] OR "Kickdown"[tw] OR "Lancer
herbicide"[tw] OR "MON 2139"[tw] OR "MON 3539"[tw] OR "MON 6000"[tw] OR "N-
(Phosphonomethyl)glycine"[tw] OR "N-(phosphonomethyl)-Glycine"[tw] OR "N-
Phosphomethylglycine"[tw] OR "N-Phosphonomethylglycine"[tw] OR "Phorsat"[tw] OR
"Phosphonomethylglycine"[tw] OR "Phosphonomethyliminoacetic acid"[tw] OR
"Pondmaster"[tw] OR "Rebel Garden"[tw] OR "Roundup Max"[tw] OR "Safal"[tw] OR
"Scout herbicide"[tw] OR "Silglif"[tw] OR "yerbimat"[tw]) NOT medline[sb]) OR
("Roundup"[tw] AND (monsanto[tw] OR "antifungal agents"[Pharmacological Action] OR
"antifungal agents"[MeSH Terms] OR "antifungal"[tw] OR "anti-fungal"[tw] OR "enzyme
GLYPHOSATE B-10
APPENDIX C
Database
search date Query string
inhibitors"[Pharmacological Action] OR "enzyme inhibitors"[MeSH Terms] OR
("enzyme"[tw] AND inhibitor*[tw]) OR "enzyme inhibitors"[tw] OR "enzyme inhibitor"[tw] OR
"herbicides"[Pharmacological Action] OR "herbicides"[MeSH Terms] OR "herbicides"[tw]
OR "herbicide"[tw] OR "uncoupling agents"[Pharmacological Action] OR "uncoupling
agents"[MeSH Terms] OR ("uncoupling"[tw] AND agent*[tw]) OR "uncoupling agent"[tw]
OR "uncoupling agents"[tw] OR "pesticides"[mh] OR pesticide*[tw]))))
Toxline ( "lancer herbicide" OR "mon 2139" OR "mon 3539" OR "mon 6000" OR "phorsat" OR
9/2017 "phosphonomethyliminoacetic acid" OR "rebel garden" OR "roundup max" OR "safal" OR
"scout herbicide" ) AND 2014:2017 [yr] AND ( ANEUPL [org] OR BIOSIS [org] OR CIS
[org] OR DART [org] OR EMIC [org] OR EPIDEM [org] OR FEDRIP [org] OR HEEP [org]
OR HMTC [org] OR IPA [org] OR RISKLINE [org] OR MTGABS [org] OR NIOSH [org] OR
NTIS [org] OR PESTAB [org] OR PPBIB [org] ) AND NOT PubMed [org] AND NOT pubdart
[org]
( " ( carboxymethylamino ) methylphosphonic acid" OR
"carboxymethylaminomethanephosphinic acid" OR "c k yuyos fav" OR "cp 67573" OR
"folusen" OR "forsat" OR "glialka" OR "glifosan 747" OR "glygran" OR "glyphodin a" OR
"glyphomax" OR "ground bio" OR "herbatop" OR "hm 2028" OR "kickdown" ) AND
2014:2017 [yr] AND ( ANEUPL [org] OR BIOSIS [org] OR CIS [org] OR DART [org] OR
EMIC [org] OR EPIDEM [org] OR FEDRIP [org] OR HEEP [org] OR HMTC [org] OR IPA
[org] OR RISKLINE [org] OR MTGABS [org] OR NIOSH [org] OR NTIS [org] OR PESTAB
[org] OR PPBIB [org] ) AND NOT PubMed [org] AND NOT pubdart [org]
( "glifoglex" OR "gliphosate" OR "gliz" OR "glyfos" OR "glyphosate" OR "glyphosphate" OR
"n ( phosphonomethyl ) glycine" OR "n ( phosphonomethyl ) glycine" OR "n
phosphomethylglycine" OR "n phosphonomethylglycine" OR "phosphonomethylglycine"
OR "pondmaster" OR "silglif" OR "yerbimat" ) AND 2014:2017 [yr] AND ( ANEUPL [org]
OR BIOSIS [org] OR CIS [org] OR DART [org] OR EMIC [org] OR EPIDEM [org] OR
FEDRIP [org] OR HEEP [org] OR HMTC [org] OR IPA [org] OR RISKLINE [org] OR
MTGABS [org] OR NIOSH [org] OR NTIS [org] OR PESTAB [org] OR PPBIB [org] ) AND
NOT PubMed [org] AND NOT pubdart [org]
1071-83-6 [rn] AND 2014:2017 [yr] AND ( ANEUPL [org] OR BIOSIS [org] OR CIS [org]
OR DART [org] OR EMIC [org] OR EPIDEM [org] OR FEDRIP [org] OR HEEP [org] OR
HMTC [org] OR IPA [org] OR RISKLINE [org] OR MTGABS [org] OR NIOSH [org] OR
NTIS [org] OR PESTAB [org] OR PPBIB [org] ) [not] PubMed [org] [not] pubdart [org]
( #7 NOT #4 ) AND NOT PubMed [org] AND NOT pubdart [org]
"roundup" AND 2014:2017 [yr] AND ( ANEUPL [org] OR BIOSIS [org] OR CIS [org] OR
DART [org] OR EMIC [org] OR EPIDEM [org] OR FEDRIP [org] OR HEEP [org] OR HMTC
[org] OR IPA [org] OR RISKLINE [org] OR MTGABS [org] OR NIOSH [org] OR NTIS [org]
OR PESTAB [org] OR PPBIB [org] ) [not] PubMed [org] [not] pubdart [org]
( "mon 0459" OR "40465 66 5" OR "mon 14420" OR "mon 8750" OR "roundup hi load" OR
"roundup prodry" OR "mon 8000" OR "monsanto 8000" OR "polado" OR "trisodium
hydrogen bis ( n ( phosphonatomethyl ) aminoacetate ) " ) AND 2014:2017 [yr] AND (
ANEUPL [org] OR BIOSIS [org] OR CIS [org] OR DART [org] OR EMIC [org] OR EPIDEM
[org] OR FEDRIP [org] OR HEEP [org] OR HMTC [org] OR IPA [org] OR RISKLINE [org]
OR MTGABS [org] OR NIOSH [org] OR NTIS [org] OR PESTAB [org] OR PPBIB [org] )
AND NOT PubMed [org] AND NOT pubdart [org]
( 34494-03-6 [rn] OR 70393-85-0 [rn] ) AND 2014:2017 [yr] AND ( ANEUPL [org] OR
BIOSIS [org] OR CIS [org] OR DART [org] OR EMIC [org] OR EPIDEM [org] OR FEDRIP
[org] OR HEEP [org] OR HMTC [org] OR IPA [org] OR RISKLINE [org] OR MTGABS [org]
GLYPHOSATE B-11
APPENDIX C
Database
search date Query string
OR NIOSH [org] OR NTIS [org] OR PESTAB [org] OR PPBIB [org] ) AND NOT PubMed
[org] AND NOT pubdart [org]
( "glyphosate diammonium" OR "diammonium n ( phosphonomethyl ) glycine" OR "n (
phosphonomethyl ) glycine diammonium salt" ) AND 2014:2017 [yr] AND ( ANEUPL [org]
OR BIOSIS [org] OR CIS [org] OR DART [org] OR EMIC [org] OR EPIDEM [org] OR
FEDRIP [org] OR HEEP [org] OR HMTC [org] OR IPA [org] OR RISKLINE [org] OR
MTGABS [org] OR NIOSH [org] OR NTIS [org] OR PESTAB [org] OR PPBIB [org] ) AND
NOT PubMed [org] AND NOT pubdart [org]
( "roundup weathermax" OR "touchdown forte hitech" OR "transorb r" OR "weathermax"
OR "zapp qi" OR "glyphosate potassium" OR "potassium glyphosate" OR "potassium n (
phosphonomethyl ) glycine" OR "uragan forte" OR "visionmax" OR "n ( phosphonomethyl )
glycine potassium salt" OR "glyphosate ammonium" OR "n ( phosphonomethyl ) glycine
ammonium salt" ) AND 2014:2017 [yr] AND ( ANEUPL [org] OR BIOSIS [org] OR CIS [org]
OR DART [org] OR EMIC [org] OR EPIDEM [org] OR FEDRIP [org] OR HEEP [org] OR
HMTC [org] OR IPA [org] OR RISKLINE [org] OR MTGABS [org] OR NIOSH [org] OR
NTIS [org] OR PESTAB [org] OR PPBIB [org] ) AND NOT PubMed [org] AND NOT pubdart
[org]
( "glyphosate potassium" OR "glyphosate monopotassium salt" OR "glyphosate potassium"
OR "glyphosate potassium" OR "monopotassium glyphosate" OR "roundup attack" OR
"roundup energy" OR "roundup maxload" OR "roundup original max" OR "roundup power
max" OR "roundup ultramax ii" ) AND 2014:2017 [yr] AND ( ANEUPL [org] OR BIOSIS
[org] OR CIS [org] OR DART [org] OR EMIC [org] OR EPIDEM [org] OR FEDRIP [org] OR
HEEP [org] OR HMTC [org] OR IPA [org] OR RISKLINE [org] OR MTGABS [org] OR
NIOSH [org] OR NTIS [org] OR PESTAB [org] OR PPBIB [org] ) AND NOT PubMed [org]
AND NOT pubdart [org]
( 39600-42-5 [rn] OR 39600-55-0 [rn] OR 39600-56-1 [rn] OR 39600-58-3 [rn] OR 40465-
59-6 [rn] OR 40465-64-3 [rn] OR 40465-67-6 [rn] OR 40465-70-1 [rn] OR 40465-90-5 [rn]
OR 40465-91-6 [rn] OR 70901-12-1 [rn] OR 114370-14-8 [rn] OR 69254-40-6 [rn] ) AND
2014:2017 [yr] AND ( ANEUPL [org] OR BIOSIS [org] OR CIS [org] OR DART [org] OR
EMIC [org] OR EPIDEM [org] OR FEDRIP [org] OR HEEP [org] OR HMTC [org] OR IPA
[org] OR RISKLINE [org] OR MTGABS [org] OR NIOSH [org] OR NTIS [org] OR PESTAB
[org] OR PPBIB [org] ) AND NOT PubMed [org] AND NOT pubdart [org]
( "sulphosate" OR "touchdown herbicide" OR "trimethylsulfonium carboxymethylamino
methylphosphonate" OR "trimethylsulfonium glyphosate" OR "glycine n ( phosphonomethyl
) ion ( 1 ) trimethylsulfonium" ) AND 2014:2017 [yr] AND ( ANEUPL [org] OR BIOSIS [org]
OR CIS [org] OR DART [org] OR EMIC [org] OR EPIDEM [org] OR FEDRIP [org] OR
HEEP [org] OR HMTC [org] OR IPA [org] OR RISKLINE [org] OR MTGABS [org] OR
NIOSH [org] OR NTIS [org] OR PESTAB [org] OR PPBIB [org] ) AND NOT PubMed [org]
AND NOT pubdart [org]
( "isopropylamine glyphosate" OR "glyphosate trimesium" OR "glyphosphate trimesium"
OR "avans 330" OR "glyphosate mono ( trimethylsulfonium ) salt" OR "glyphosate
trimethylsulfonium salt" OR "glyphosate trimesium" OR "medallon" OR "ouragan" OR "r
50224" OR "sc 0224" OR "sulfosate" ) AND 2014:2017 [yr] AND ( ANEUPL [org] OR
BIOSIS [org] OR CIS [org] OR DART [org] OR EMIC [org] OR EPIDEM [org] OR FEDRIP
[org] OR HEEP [org] OR HMTC [org] OR IPA [org] OR RISKLINE [org] OR MTGABS [org]
OR NIOSH [org] OR NTIS [org] OR PESTAB [org] OR PPBIB [org] ) AND NOT PubMed
[org] AND NOT pubdart [org]
GLYPHOSATE B-12
APPENDIX C
Database
search date Query string
( "n ( phosphonomethyl ) glycine monoisopropylamine salt" OR "nitosorg" OR "utal" OR
"utal ( herbicide ) " OR "vision ( herbicide ) " OR "2 propanamine compd with n (
phosphonomethyl ) glycine ( 1 1 ) " OR "glycine n ( phosphonomethyl ) compd with 2
propanamine ( 1 1 ) " OR "n ( phosphonomethyl ) glycine compound with 2 propylamine ( 1
1 ) " ) AND 2014:2017 [yr] AND ( ANEUPL [org] OR BIOSIS [org] OR CIS [org] OR DART
[org] OR EMIC [org] OR EPIDEM [org] OR FEDRIP [org] OR HEEP [org] OR HMTC [org]
OR IPA [org] OR RISKLINE [org] OR MTGABS [org] OR NIOSH [org] OR NTIS [org] OR
PESTAB [org] OR PPBIB [org] ) AND NOT PubMed [org] AND NOT pubdart [org]
( "glyphosate mono ( isopropylamine ) salt" OR "glyphosate isopropylammonium" OR
"glyphosate mono ( isopropylammonium ) " OR "landmaster" OR "mon 139" OR "mon 39"
OR "n ( phosphonomethyl ) glycine isopropylamine salt" OR "n ( phosphonomethyl )
glycine isopropylammonium salt" ) AND 2014:2017 [yr] AND ( ANEUPL [org] OR BIOSIS
[org] OR CIS [org] OR DART [org] OR EMIC [org] OR EPIDEM [org] OR FEDRIP [org] OR
HEEP [org] OR HMTC [org] OR IPA [org] OR RISKLINE [org] OR MTGABS [org] OR
NIOSH [org] OR NTIS [org] OR PESTAB [org] OR PPBIB [org] ) AND NOT PubMed [org]
AND NOT pubdart [org]
( "glyphosate isopropylammonium" OR "glyphosate isopropylamine salt" OR "azural at" OR
"cp 70139" OR "fosulen" OR "glifosato estrella" OR "glycel" OR "glycine n (
phosphonomethyl ) cmpd with 2 propanamine ( 1 1 ) " OR "glyfos au" OR "glyfos bio" OR
"glyphosate isopropylamine salt" ) AND 2014:2017 [yr] AND ( ANEUPL [org] OR BIOSIS
[org] OR CIS [org] OR DART [org] OR EMIC [org] OR EPIDEM [org] OR FEDRIP [org] OR
HEEP [org] OR HMTC [org] OR IPA [org] OR RISKLINE [org] OR MTGABS [org] OR
NIOSH [org] OR NTIS [org] OR PESTAB [org] OR PPBIB [org] ) AND NOT PubMed [org]
AND NOT pubdart [org]
( 38641-94-0 [rn] OR 81591-81-3 [rn] ) AND 2014:2017 [yr] AND ( ANEUPL [org] OR
BIOSIS [org] OR CIS [org] OR DART [org] OR EMIC [org] OR EPIDEM [org] OR FEDRIP
[org] OR HEEP [org] OR HMTC [org] OR IPA [org] OR RISKLINE [org] OR MTGABS [org]
OR NIOSH [org] OR NTIS [org] OR PESTAB [org] OR PPBIB [org] ) AND NOT PubMed
[org] AND NOT pubdart [org]
2/2015 "Glifoglex" OR "gliphosate" OR "Gliz" OR "Glyfos" OR "Glyphosate" OR "Glyphosphate"
OR "N-(Phosphonomethyl)glycine" OR "N-(phosphonomethyl)-Glycine" OR "N-
Phosphomethylglycine" OR "N-Phosphonomethylglycine" OR "Phosphonomethylglycine"
OR "Pondmaster" OR "Silglif" OR "yerbimat"
"(Carboxymethylamino)methylphosphonic acid" OR
"Carboxymethylaminomethanephosphinic acid" OR "C-K Yuyos FAV" OR "CP 67573" OR
"Folusen" OR "Forsat" OR "Glialka" OR "Glifosan 747" OR "GlyGran" OR "Glyphodin A"
OR "Glyphomax" OR "Ground Bio" OR "Herbatop" OR "HM 2028" OR "Kickdown"
"Lancer herbicide" OR "MON 2139" OR "MON 3539" OR "MON 6000" OR "Phorsat" OR
"Phosphonomethyliminoacetic acid" OR "Rebel Garden" OR "Roundup Max" OR "Safal"
OR "Scout herbicide"
"roundup"
34494-03-6[rn] OR 70393-85-0[rn]
"MON 0459" OR "40465-66-5" OR "MON 14420" OR "MON 8750" OR "Roundup Hi-Load"
OR "Roundup PRODry" OR "MON 8000" OR "Monsanto 8000" OR "Polado" OR
"Trisodium hydrogen bis(N-(phosphonatomethyl)aminoacetate)"
GLYPHOSATE B-13
APPENDIX C
Database
search date Query string
39600-42-5[rn] OR 39600-55-0[rn] OR 39600-56-1[rn] OR 39600-58-3[rn] OR 40465-59-
6[rn] OR 40465-64-3[rn] OR 40465-67-6[rn] OR 40465-70-1[rn] OR 40465-90-5[rn] OR
40465-91-6[rn] OR 70901-12-1[rn] OR 114370-14-8[rn] OR 69254-40-6[rn]
"Glyphosate potassium" OR "Glyphosate monopotassium salt" OR "Glyphosate
potassium" OR "Glyphosate-potassium" OR "Monopotassium glyphosate" OR "Roundup
Attack" OR "Roundup Energy" OR "Roundup Maxload" OR "Roundup Original Max" OR
"Roundup Power Max" OR "Roundup Ultramax II"
"Roundup Weathermax" OR "Touchdown Forte HiTech" OR "Transorb R" OR
"Weathermax" OR "Zapp Qi" OR "Glyphosate-potassium" OR "Potassium glyphosate" OR
"Potassium N-(phosphonomethyl)glycine" OR "Uragan Forte" OR "VisionMAX" OR "N-
(phosphonomethyl)glycine potassium salt" OR "Glyphosate ammonium" OR "N-
(phosphonomethyl)glycine ammonium salt"
"Glyphosate-diammonium" OR "Diammonium N-(phosphonomethyl)glycine" OR "N-
(phosphonomethyl)glycine diammonium salt"
38641-94-0[rn] OR 81591-81-3[rn]
"Glyphosate-isopropylammonium" OR "Glyphosate isopropylamine salt" OR "Azural AT"
OR "CP 70139" OR "Fosulen" OR "Glifosato estrella" OR "Glycel" OR "Glycine, N-
(phosphonomethyl)-, cmpd with 2-propanamine (1:1)" OR "Glyfos AU" OR "Glyfos BIO"
OR "Glyphosate isopropylamine salt"
"Glyphosate mono(isopropylamine) salt" OR "Glyphosate-isopropylammonium" OR
"Glyphosate-mono(isopropylammonium)" OR "Landmaster" OR "MON 139" OR "MON 39"
OR "N-(Phosphonomethyl)glycine isopropylamine salt" OR "N-(Phosphonomethyl)glycine
isopropylammonium salt"
"N-(Phosphonomethyl)glycine monoisopropylamine salt" OR "Nitosorg" OR "Utal" OR "Utal
(herbicide)" OR "Vision (herbicide)" OR "2-Propanamine, compd, with N-
(phosphonomethyl)glycine (1:1)" OR "Glycine, N-(phosphonomethyl)-, compd. with 2-
propanamine (1:1)" OR "N-(Phosphonomethyl)glycine, compound with 2-propylamine
(1:1)"
"Isopropylamine glyphosate" OR "Glyphosate-trimesium" OR "Glyphosphate-trimesium"
OR "Avans 330" OR "Glyphosate mono(trimethylsulfonium) salt" OR "Glyphosate
trimethylsulfonium salt" OR "Glyphosate-trimesium" OR "Medallon" OR "Ouragan" OR "R
50224" OR "SC 0224" OR "Sulfosate"
"Sulphosate" OR "Touchdown herbicide" OR "Trimethylsulfonium carboxymethylamino-
methylphosphonate” OR “Trimethylsulfonium glyphosate” OR “Glycine, N- N-
phosphonemethyl)-, ion(1-), trimethylsulfonium”
Toxcenter L1 9995 SEA 1071-83-6
9/2017 L2 92 SEA 34494-03-6 OR 40465-66-5 OR 70393-85-0
L3 80 SEA 39600-42-5 OR 39600-55-0 OR 39600-56-1 OR 39600-58-3 OR
40465-59-6 OR 40465-64-3 OR 40465-67-6 OR 40465-70-1 OR
40465-90-5 OR 40465-91-6
L4 101 SEA 70901-12-1 OR 114370-14-8 OR 69254-40-6
L5 2022 SEA 38641-94-0 OR 81591-81-3
L6 10037 SEA L1 OR L2 OR L3 OR L4
L7 6132 SEA L6 NOT (TSCATS/FS OR PATENT/DT)
L8 2048 SEA L6 AND (PY>2013 OR ED>=20150201)
L9 1260 SEA L7 AND (PY>2013 OR ED>=20150201)
L10 751 SEA L5 NOT L6
GLYPHOSATE B-14
APPENDIX C
Database
search date Query string
L11 530 SEA L10 NOT (TSCATS/FS OR PATENT/DT)
L12 63 SEA L11 AND (PY>2013 OR ED>=20150201)
L13 56 SEA L9 AND (CANCER? OR CARCINOG? OR CARCINOM? OR
COCARCINOG?
OR LYMPHOMA? OR NEOPLAS? OR ONCOGEN? OR PRECANCER? OR
TUMOR?
OR TUMOUR?)
L14 6 SEA L12 AND (CANCER? OR CARCINOG? OR CARCINOM? OR
COCARCINOG?
OR LYMPHOMA? OR NEOPLAS? OR ONCOGEN? OR PRECANCER? OR
TUMOR?
OR TUMOUR?)
L15 16 SEA L13 AND MEDLINE/FS
L16 40 SEA L13 NOT L15
L17 44 DUP REM L15 L16 (12 DUPLICATES REMOVED)
ANSWERS '1-44' FROM FILE TOXCENTER
L*** DEL 16 S L13 AND MEDLINE/FS
L*** DEL 16 S L13 AND MEDLINE/FS
L18 16 SEA L17
L*** DEL 40 S L13 NOT L15
L*** DEL 40 S L13 NOT L15
L19 28 SEA L17
L20 28 SEA (L18 OR L19) NOT MEDLINE/FS
D SCAN L20
L21 401072 SEA 14 NOT MEDLINE/FS
L22 6 SEA L14 NOT MEDLINE/FS
L23 6 DUP REM L22 (0 DUPLICATES REMOVED)
ANSWERS '1-6' FROM FILE TOXCENTER
D SCAN L23
FILE 'MEDLINE' ENTERED AT 19:10:42 ON 14 SEP 2017
CHARGED TO COST=EH011.10.01
L24 QUE ACROCHORDON OR ACROCHORDONS OR ADENOMATOSIS OR
ADENOMATOUS
OR ADENOSIS OR AMYLOIDOSES OR AMYLOIDOSIS OR ANAPLASIA OR
ANGIOENDOTHELIOMATOSIS OR ANGIOMATOSIS OR BUSCHKE-
LOWENSTEIN
OR CANCER OR CANCEROUS OR CANCERS OR CARCINOGEN
L25 QUE CARCINOGENESIS OR CARCINOGENIC OR CARCINOGENICITY OR
CARCINOGENS OR CARCINOID OR CARCINOMATOSIS OR CHERUBISM
OR CIN
OR CLL OR COCARCINOGENESIS OR DERMOID OR DYSMYELOPOIESIS
OR
ENCHONDROMATOSIS OR EPIDERMOID OR ERYTHROLEUKAEMIA OR
ERYTHROLE
UKAEMIAS
L26 QUE ERYTHROLEUKEMIA OR ERYTHROLEUKEMIAS OR
ERYTHROPLAKIA OR
ERYTHROPLAKIAS OR ERYTHROPLASIA OR ESSENTIAL-
THROMBOCYTHEMIA
OR EXOSTOSIS OR FIBROADENOSIS OR FIBROID OR FIBROIDS OR
GLYPHOSATE B-15
APPENDIX C
Database
search date Query string
FIBROMATOSIS OR GLIOMATOSIS OR GLOMANGIOMATOSIS OR
GRANULOMATOS
IS
L27 QUE GYNAECOMASTIA OR GYNECOMASTIA OR HEMANGIOMATOSIS
OR
HODGKIN OR HODGKINS OR LEIOMYOMATOSIS OR LEUKAEMIA OR
LEUKAEMIA
S OR LEUKEMIA OR LEUKEMIAS OR LEUKOPLAKIA OR LEUKOPLAKIAS
OR
LEUKOSTASIS OR LIPOBLASTOMATOSIS OR LIPOMATOSIS
L28 QUE LYMPHANGIOLEIOMYOMATOSIS OR LYMPHANGIOMATOSIS OR
LYMPHANGIO
MYOMATOSIS OR LYMPHOPROLIFERATION OR
LYMPHOPROLIFERATIONS OR
LYMPHOPROLIFERATIVE OR LYMPHOSCINTIGRAPHIC OR
LYMPHOSCINTIGRAPH
Y OR MACROGLOBULINEMIA OR MACROGLOBULINEMIAS
L29 QUE MALIGNANCIES OR MALIGNANCY OR MALIGNANT OR
MASTOCYTOSIS OR
MEIGS-SYNDROME OR MELANOMATOSIS OR MENINGIOMATOSIS OR
METAPLASI
A OR MICROMETASTASES OR MICROMETASTASIS OR MYCOSIS-
FUNGOIDES
OR MYELODYSPLASIA OR MYELODYSPLASIAS
L30 QUE MYELODYSPLASTIC OR MYELOFIBROSIS OR MYELOMATOSIS OR
MYELOPROLIFERATION OR MYELOPROLIFERATIONS OR
MYELOPROLIFERATIVE
OR MYELOSUPPRESSION OR MYOFIBROMATOSIS OR NEOPLASIA OR
NEOPLASM OR NEOPLASMS OR NEOPLASTIC OR NEURILEMMOMATOSIS
L31 QUE NEUROFIBROMATOSIS OR NEURONEVUS OR NONHODGKIN OR
NONHODGKIN
S OR NONSEMINOMATOUS OR NSCLC OR ONCOGENE-FUSION OR
OPSOCLONUS-
MYOCLONUS OR PAPILLOMATA OR PAPILLOMATOSIS OR
PARANEOPLASTIC
OR PEUTZ-JEGHERS OR POLYPOSIS OR PRECANCER
L32 QUE PRECANCEROUS OR SARCOMATOSIS OR SCHWANNOMATOSIS
OR
SEMINOMATOUS OR SEZARY-SYNDROME OR STRUMA-OVARII OR
TUMOR OR
TUMORGENESIS OR TUMORGENIC OR TUMORIGENESIS OR
TUMORIGENIC OR
TUMOR-MARKER OR TUMOR-MARKERS OR TUMOROGENESIS
L33 QUE TUMOROGENIC OR TUMORS OR TUMOUR OR TUMOURS OR
WALDENSTROM
OR WALDENSTROMS OR "5Q-SYNDROME" OR "WAGR SYNDROME" OR
(ASCO
NOT FUNGI) OR (SENTINEL-LYMPH-NODE NOT BIOPSY)
L34 QUE L24 OR L25 OR L26 OR L27 OR L28 OR L29 OR L30 OR L31 OR
L32 OR L33
GLYPHOSATE B-16
APPENDIX C
Database
search date Query string
DIS COST
FILE 'TOXCENTER' ENTERED AT 19:12:52 ON 14 SEP 2017
CHARGED TO COST=EH011.10.01
L47 1 SEA L9 AND ?IOMA
DIS COST
L48 26 SEA L9 AND (?AOMA OR ?BOMA OR ?COMA OR ?DOMA OR ?EOMA OR
?FOMA
OR ?GOMA OR ?HOMA OR ?IOMA OR ?JOMA OR ?KOMA OR ?LOMA OR
?MOMA
OR ?NOMA OR ?OOMA OR ?POMA OR ?QOMA OR ?ROMA OR ?SOMA OR
?TOMA
OR ?UOMA OR ?VOMA OR ?WOMA)
L49 0 SEA L9 AND (?XOMA OR ?YOMA OR ?ZOMA OR ?AOMAS OR ?BOMAS
OR
?COMAS OR ?DOMAS OR ?EOMAS OR ?FOMAS OR ?GOMAS OR ?HOMAS
OR
?IOMAS OR ?JOMAS OR ?KOMAS OR ?LOMAS OR ?MOMAS OR ?NOMAS
OR
?OOMAS OR ?POMAS OR ?QOMAS OR ?ROMAS)
L50 0 SEA L9 AND (?SOMAS OR ?TOMAS OR ?UOMAS OR ?VOMAS OR
?WOMAS OR
?XOMAS OR ?YOMAS OR ?ZOMAS)
L51 48 SEA L9 AND L34
L52 68 SEA L48 OR L49 OR L50 OR L51
L53 16 SEA L52 NOT L13
L54 20 SEA L52 AND MEDLINE/FS
L55 7 SEA L53 AND MEDLINE/FS
L56 12 DUP REM L53 (4 DUPLICATES REMOVED)
ANSWERS '1-12' FROM FILE TOXCENTER
D SCAN L56
L57 6 SEA L12 AND L34
L58 2 SEA L12 AND (?AOMA OR ?BOMA OR ?COMA OR ?DOMA OR ?EOMA OR
?FOMA OR ?GOMA OR ?HOMA OR ?IOMA OR ?JOMA OR ?KOMA OR
?LOMA OR
?MOMA OR ?NOMA OR ?OOMA OR ?POMA OR ?QOMA OR ?ROMA OR
?SOMA OR
?TOMA OR ?UOMA OR ?VOMA OR ?WOMA)
L59 0 SEA L12 AND (?XOMA OR ?YOMA OR ?ZOMA OR ?AOMAS OR ?BOMAS
OR
?COMAS OR ?DOMAS OR ?EOMAS OR ?FOMAS OR ?GOMAS OR ?HOMAS
OR
?IOMAS OR ?JOMAS OR ?KOMAS OR ?LOMAS OR ?MOMAS OR ?NOMAS
OR
?OOMAS OR ?POMAS OR ?QOMAS OR ?ROMAS)
L60 0 SEA L12 AND (?SOMAS OR ?TOMAS OR ?UOMAS OR ?VOMAS OR
?WOMAS OR
?XOMAS OR ?YOMAS OR ?ZOMAS)
L61 8 SEA L57 OR L58
L62 8 SEA L61 NOT (L13 OR L52)
L63 7 DUP REM L62 (1 DUPLICATE REMOVED)
GLYPHOSATE B-17
APPENDIX C
Database
search date Query string
ANSWERS '1-7' FROM FILE TOXCENTER
D SCAN L63
2/2017 FILE 'TOXCENTER' ENTERED AT 19:21:56 ON 18 FEB 2015
CHARGED TO COST=EH011.05.01.01
L1 8342 SEA 1071-83-6
L2 63 SEA 34494-03-6 OR 40465-66-5 OR 70393-85-0
L3 8 SEA L2 NOT L1
L4 53 SEA 39600-42-5 OR 39600-55-0 OR 39600-56-1 OR 39600-58-3 OR
40465-59-6 OR 40465-64-3 OR 40465-67-6 OR 40465-70-1 OR
40465-90-5 OR 40465-91-6
L5 59 SEA 70901-12-1 OR 114370-14-8 OR 69254-40-6
L6 1828 SEA 38641-94-0 OR 81591-81-3
L7 8369 SEA L1 OR L2 OR L4 OR L5
L8 5041 SEA L7 NOT (PATENT/DT OR TSCATS/FS)
ACT TOXQUERY/Q
---------
L9 QUE (CHRONIC OR IMMUNOTOX? OR NEUROTOX? OR TOXICOKIN? OR
BIOMARKER? OR NEUROLOG?)
L10 QUE (PHARMACOKIN? OR SUBCHRONIC OR PBPK OR
EPIDEMIOLOGY/ST,CT,
IT)
L11 QUE (ACUTE OR SUBACUTE OR LD50# OR LD(W)50 OR LC50# OR
LC(W)50)
L12 QUE (TOXICITY OR ADVERSE OR POISONING)/ST,CT,IT
L13 QUE (INHAL? OR PULMON? OR NASAL? OR LUNG? OR RESPIR?)
L14 QUE ((OCCUPATION? OR WORKPLACE? OR WORKER?) AND EXPOS?)
L15 QUE (ORAL OR ORALLY OR INGEST? OR GAVAGE? OR DIET OR DIETS
OR
DIETARY OR DRINKING(W)WATER?)
L16 QUE (MAXIMUM AND CONCENTRATION? AND (ALLOWABLE OR
PERMISSIBLE))
L17 QUE (ABORT? OR ABNORMALIT? OR EMBRYO? OR CLEFT? OR FETUS?)
L18 QUE (FOETUS? OR FETAL? OR FOETAL? OR FERTIL? OR MALFORM?
OR
OVUM?)
L19 QUE (OVA OR OVARY OR PLACENTA? OR PREGNAN? OR PRENATAL?)
L20 QUE (PERINATAL? OR POSTNATAL? OR REPRODUC? OR STERIL? OR
TERATOGEN?)
L21 QUE (SPERM OR SPERMAC? OR SPERMAG? OR SPERMATI? OR
SPERMAS? OR
SPERMATOB? OR SPERMATOC? OR SPERMATOG?)
L22 QUE (SPERMATOI? OR SPERMATOL? OR SPERMATOR? OR
SPERMATOX? OR
SPERMATOZ? OR SPERMATU? OR SPERMI? OR SPERMO?)
L23 QUE (NEONAT? OR NEWBORN? OR DEVELOPMENT OR
DEVELOPMENTAL?)
L24 QUE (ENDOCRIN? AND DISRUPT?)
L25 QUE (ZYGOTE? OR CHILD OR CHILDREN OR ADOLESCEN? OR
INFANT?)
L26 QUE (WEAN? OR OFFSPRING OR AGE(W)FACTOR?)
GLYPHOSATE B-18
APPENDIX C
Database
search date Query string
L27 QUE (DERMAL? OR DERMIS OR SKIN OR EPIDERM? OR CUTANEOUS?)
L28 QUE (CARCINOG? OR COCARCINOG? OR CANCER? OR PRECANCER?
OR
NEOPLAS?)
L29 QUE (TUMOR? OR TUMOUR? OR ONCOGEN? OR LYMPHOMA? OR
CARCINOM?)
L30 QUE (GENETOX? OR GENOTOX? OR MUTAGEN? OR
GENETIC(W)TOXIC?)
L31 QUE (NEPHROTOX? OR HEPATOTOX?)
L32 QUE (ENDOCRIN? OR ESTROGEN? OR ANDROGEN? OR HORMON?)
L33 QUE (OCCUPATION? OR WORKER? OR WORKPLACE? OR EPIDEM?)
L34 QUE L9 OR L10 OR L11 OR L12 OR L13 OR L14 OR L15 OR L16 OR L17
OR L18 OR L19 OR L20 OR L21 OR L22 OR L23 OR L24 OR L25 OR L26
OR L27 OR L28 OR L29 OR L30 OR L31 OR L32 OR L33
L35 QUE (RAT OR RATS OR MOUSE OR MICE OR GUINEA(W)PIG? OR
MURIDAE
OR DOG OR DOGS OR RABBIT? OR HAMSTER? OR PIG OR PIGS OR
SWINE
OR PORCINE OR MONKEY? OR MACAQUE?)
L36 QUE (MARMOSET? OR FERRET? OR GERBIL? OR RODENT? OR
LAGOMORPHA
OR BABOON? OR CANINE OR CAT OR CATS OR FELINE OR MURINE)
L37 QUE L34 OR L35 OR L36
L38 QUE (HUMAN OR HUMANS OR HOMINIDAE OR MAMMALS OR MAMMAL?
OR
PRIMATES OR PRIMATE?)
L39 QUE L37 OR L38
---------
L40 2675 SEA L8 AND L37
L41 525 SEA L40 AND MEDLINE/FS
L42 833 SEA L40 AND BIOSIS/FS
L43 1263 SEA L40 AND CAPLUS/FS
L44 0 SEA L40 AND IPA/FS
L45 54 SEA L40 NOT (L41 OR L42 OR L43)
L46 2064 DUP REM L41 L42 L43 L45 (611 DUPLICATES REMOVED)
ANSWERS '1-2064' FROM FILE TOXCENTER
L*** DEL 525 S L40 AND MEDLINE/FS
L*** DEL 525 S L40 AND MEDLINE/FS
L47 525 SEA L46
L*** DEL 833 S L40 AND BIOSIS/FS
L*** DEL 833 S L40 AND BIOSIS/FS
L48 644 SEA L46
L*** DEL 1263 S L40 AND CAPLUS/FS
L*** DEL 1263 S L40 AND CAPLUS/FS
L49 859 SEA L46
L*** DEL 54 S L40 NOT (L41 OR L42 OR L43)
L*** DEL 54 S L40 NOT (L41 OR L42 OR L43)
L50 36 SEA L46
L51 1539 SEA (L47 OR L48 OR L49 OR L50) NOT MEDLINE/FS
L52 1532 SEA L51 AND L1
GLYPHOSATE B-19
APPENDIX C
Database
search date Query string
L53 7 SEA L51 NOT L52
D SCAN L53
L54 688 SEA L6 NOT L7
L55 485 SEA L54 NOT (PATENT/DT OR TSCATS/FS)
L56 314 SEA L55 AND L37
L57 0 SEA L56 AND MEDLINE/FS
L58 85 SEA L56 AND BIOSIS/FS
L59 218 SEA L56 AND CAPLUS/FS
L60 1 SEA L56 AND IPA/FS
L61 274 DUP REM L56 (40 DUPLICATES REMOVED)
ANSWERS '1-274' FROM FILE TOXCENTER
D SCAN L52
APPENDIX C
aSeveral versions of the TSCATS database were searched, as needed, by CASRN including TSCATS1 via Toxline
(no date limit), TSCATS2 via https://yosemite.epa.gov/oppts/epatscat8.nsf/ReportSearch?OpenForm (date restricted
by EPA receipt date), and TSCATS via CDAT (date restricted by ‘Mail Received Date Range’), as well as google for
recent TSCA submissions.
Following the publication of the draft profile and receipt of public comments, ATSDR conducted an
updated literature review to capture any references published after the conclusion of the original literature
review. The updated literature review searches occurred in September and October 2019 using the
following sources:
GLYPHOSATE B-21
APPENDIX C
• Toxline
• IPA
• Science Direct
• PubMed
• BIOSIS
• MEDLINE
• SciFinder
In each database, searches were limited to references published from 2017 (i.e., the year the literature
searches for glyphosate were last conducted) to the present date. Table B-4 includes the search strings
used in each of these searches.
APPENDIX C
APPENDIX C
APPENDIX C
APPENDIX C
APPENDIX C
APPENDIX C
APPENDIX C
APPENDIX C
APPENDIX C
APPENDIX C
APPENDIX C
APPENDIX C
A two-step process was used to screen the literature search to identify relevant studies on glyphosate:
• Title and abstract screen
• Full text screen
Title and Abstract Screen. Within the reference library, titles and abstracts were screened manually for
relevance. Studies that were considered relevant (see Table B-1 for inclusion criteria) were moved to the
second step of the literature screening process. Studies were excluded when the title and/or abstract
clearly indicated that the study was not relevant to the toxicological profile.
APPENDIX C
Full Text Screen. The second step in the literature screening process was a full text review of individual
studies considered relevant in the title and abstract screen step. Each study was reviewed to determine
whether it was relevant for inclusion in the toxicological profile.
A summary of the results of the literature search and screening is presented in Figure B- and Figure B-2..
GLYPHOSATE B-35
APPENDIX C
Figure B-1. February 2015 and September 2017 Literature Search Results and
Screen for Glyphosate
GLYPHOSATE B-36
APPENDIX C
Figure B-2. September 2019 Supplemental Literature Search Results and Screen
for Glyphosate
Literature Search
This chapter provides an overview of U.S. exposures, a summary of health effects based on evaluations of
existing toxicologic, epidemiologic, and toxicokinetic information, and an overview of the minimal risk
levels. This is designed to present interpretive, weight-of-evidence discussions for human health
endpoints by addressing the following questions:
3. What exposure conditions are likely to be of concern to humans, especially around hazardous
waste sites?
Where sufficient toxicologic information is available, ATSDR derives MRLs for inhalation and oral
routes of entry at each duration of exposure (acute, intermediate, and chronic). These MRLs are not
meant to support regulatory action, but to acquaint health professionals with exposure levels at which
adverse health effects are not expected to occur in humans.
MRLs should help physicians and public health officials determine the safety of a community living near
a hazardous substance emission, given the concentration of a contaminant in air or the estimated daily
dose in water. MRLs are based largely on toxicological studies in animals and on reports of human
occupational exposure.
MRL users should be familiar with the toxicologic information on which the number is based.
Section 1.2, Summary of Health Effects, contains basic information known about the substance. Other
sections, such as Section 3.2 Children and Other Populations that are Unusually Susceptible and
Section 3.4 Interactions with Other Substances, provide important supplemental information.
MRL users should also understand the MRL derivation methodology. MRLs are derived using a
modified version of the risk assessment methodology that the Environmental Protection Agency (EPA)
provides (Barnes and Dourson 1988) to determine reference doses (RfDs) for lifetime exposure.
To derive an MRL, ATSDR generally selects the most sensitive endpoint which, in its best judgement,
represents the most sensitive human health effect for a given exposure route and duration. ATSDR
cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available
for all potential systemic, neurological, and developmental effects. If this information and reliable
quantitative data on the chosen endpoint are available, ATSDR derives an MRL using the most sensitive
species (when information from multiple species is available) with the highest no-observed-adverse-effect
level (NOAEL) that does not exceed any adverse effect levels. When a NOAEL is not available, a
lowest-observed-adverse-effect level (LOAEL) can be used to derive an MRL, and an uncertainty factor
of 10 must be employed. Additional uncertainty factors of 10 must be used both for human variability to
protect sensitive subpopulations (people who are most susceptible to the health effects caused by the
substance) and for interspecies variability (extrapolation from animals to humans). In deriving an MRL,
GLYPHOSATE B-2
APPENDIX C
these individual uncertainty factors are multiplied together. The product is then divided into the
inhalation concentration or oral dosage selected from the study. Uncertainty factors used in developing a
substance-specific MRL are provided in the footnotes of the levels of significant exposure (LSE) tables
that are provided in Chapter 2. Detailed discussions of the MRLs are presented in Appendix A.
Tables and figures are used to summarize health effects and illustrate graphically levels of exposure
associated with those effects. These levels cover health effects observed at increasing dose
concentrations and durations, differences in response by species and MRLs to humans for noncancer
endpoints. The LSE tables and figures can be used for a quick review of the health effects and to locate
data for a specific exposure scenario. The LSE tables and figures should always be used in conjunction
with the text. All entries in these tables and figures represent studies that provide reliable, quantitative
estimates of NOAELs, LOAELs, or Cancer Effect Levels (CELs).
The legends presented below demonstrate the application of these tables and figures. Representative
examples of LSE tables and figures follow. The numbers in the left column of the legends correspond to
the numbers in the example table and figure.
TABLE LEGEND
See Sample LSE Table (page C-5)
(1) Route of exposure. One of the first considerations when reviewing the toxicity of a substance
using these tables and figures should be the relevant and appropriate route of exposure.
Typically, when sufficient data exist, three LSE tables and two LSE figures are presented in the
document. The three LSE tables present data on the three principal routes of exposure
(i.e., inhalation, oral, and dermal). LSE figures are limited to the inhalation and oral routes. Not
all substances will have data on each route of exposure and will not, therefore, have all five of the
tables and figures. Profiles with more than one chemical may have more LSE tables and figures.
(2) Exposure period. Three exposure periods—acute (<15 days), intermediate (15–364 days), and
chronic (≥365 days)—are presented within each relevant route of exposure. In this example, two
oral studies of chronic-duration exposure are reported. For quick reference to health effects
occurring from a known length of exposure, locate the applicable exposure period within the LSE
table and figure.
(3) Figure key. Each key number in the LSE table links study information to one or more data points
using the same key number in the corresponding LSE figure. In this example, the study
represented by key number 51 identified NOAELs and less serious LOAELs (also see the three
"51R" data points in sample LSE Figure 2-X).
(4) Species (strain) No./group. The test species (and strain), whether animal or human, are identified
in this column. The column also contains information on the number of subjects and sex per
group. Chapter 1, Relevance to Public Health, covers the relevance of animal data to human
toxicity and Section 3.1, Toxicokinetics, contains any available information on comparative
toxicokinetics. Although NOAELs and LOAELs are species specific, the levels are extrapolated
to equivalent human doses to derive an MRL.
GLYPHOSATE B-3
APPENDIX C
(5) Exposure parameters/doses. The duration of the study and exposure regimens are provided in
these columns. This permits comparison of NOAELs and LOAELs from different studies. In
this case (key number 51), rats were orally exposed to “Chemical X” via feed for 2 years. For a
more complete review of the dosing regimen, refer to the appropriate sections of the text or the
original reference paper (i.e., Aida et al. 1992).
(6) Parameters monitored. This column lists the parameters used to assess health effects. Parameters
monitored could include serum (blood) chemistry (BC), behavioral (BH), biochemical changes
(BI), body weight (BW), clinical signs (CS), developmental toxicity (DX), enzyme activity (EA),
food intake (FI), fetal toxicity (FX), gross necropsy (GN), hematology (HE), histopathology
(HP), lethality (LE), maternal toxicity (MX), organ function (OF), ophthalmology (OP), organ
weight (OW), teratogenicity (TG), urinalysis (UR), and water intake (WI).
(7) Endpoint. This column lists the endpoint examined. The major categories of health endpoints
included in LSE tables and figures are death, body weight, respiratory, cardiovascular,
gastrointestinal, hematological, musculoskeletal, hepatic, renal, dermal, ocular, endocrine,
immunological, neurological, reproductive, developmental, other noncancer, and cancer. "Other
noncancer" refers to any effect (e.g., alterations in blood glucose levels) not covered in these
systems. In the example of key number 51, three endpoints (body weight, hematological, and
hepatic) were investigated.
(8) NOAEL. A NOAEL is the highest exposure level at which no adverse effects were seen in the
organ system studied. The body weight effect reported in key number 51 is a NOAEL at
25.5 mg/kg/day. NOAELs are not reported for cancer and death; with the exception of these two
endpoints, this field is left blank if no NOAEL was identified in the study.
(9) LOAEL. A LOAEL is the lowest dose used in the study that caused an adverse health effect.
LOAELs have been classified into "Less Serious" and "Serious" effects. These distinctions help
readers identify the levels of exposure at which adverse health effects first appear and the
gradation of effects with increasing dose. A brief description of the specific endpoint used to
quantify the adverse effect accompanies the LOAEL. Key number 51 reports a less serious
LOAEL of 6.1 mg/kg/day for the hepatic system, which was used to derive a chronic exposure,
oral MRL of 0.008 mg/kg/day (see footnote "c"). MRLs are not derived from serious LOAELs.
A cancer effect level (CEL) is the lowest exposure level associated with the onset of
carcinogenesis in experimental or epidemiologic studies. CELs are always considered serious
effects. The LSE tables and figures do not contain NOAELs for cancer, but the text may report
doses not causing measurable cancer increases. If no LOAEL/CEL values were identified in the
study, this field is left blank.
(10) Reference. The complete reference citation is provided in Chapter 8 of the profile.
(11) Footnotes. Explanations of abbreviations or reference notes for data in the LSE tables are found
in the footnotes. For example, footnote "c" indicates that the LOAEL of 6.1 mg/kg/day in key
number 51 was used to derive an oral MRL of 0.008 mg/kg/day.
GLYPHOSATE B-4
APPENDIX C
FIGURE LEGEND
See Sample LSE Figure (page C-6)
LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the
reader quickly compare health effects according to exposure concentrations for particular exposure
periods.
(13) Exposure period. The same exposure periods appear as in the LSE table. In this example, health
effects observed within the chronic exposure period are illustrated.
(14) Endpoint. These are the categories of health effects for which reliable quantitative data exist.
The same health effect endpoints appear in the LSE table.
(15) Levels of exposure. Concentrations or doses for each health effect in the LSE tables are
graphically displayed in the LSE figures. Exposure concentration or dose is measured on the log
scale "y" axis. Inhalation exposure is reported in mg/m3 or ppm and oral exposure is reported in
mg/kg/day.
(16) LOAEL. In this example, the half-shaded circle that is designated 51R identifies a LOAEL
critical endpoint in the rat upon which a chronic oral exposure MRL is based. The key number
51 corresponds to the entry in the LSE table. The dashed descending arrow indicates the
extrapolation from the exposure level of 6.1 mg/kg/day (see entry 51 in the sample LSE table) to
the MRL of 0.008 mg/kg/day (see footnote "c" in the sample LSE table).
(17) CEL. Key number 59R is one of studies for which CELs were derived. The diamond symbol
refers to a CEL for the test species (rat). The number 59 corresponds to the entry in the LSE
table.
(18) Key to LSE figure. The key provides the abbreviations and symbols used in the figure.
GLYPHOSATE C-5
APPENDIX C
GLYPHOSATE C-6
APPENDIX C
GLYPHOSATE D-1
Chapter 1: Relevance to Public Health: The Relevance to Public Health Section provides an overview
of exposure and health effects and evaluates, interprets, and assesses the significance of toxicity
data to human health. A table listing minimal risk levels (MRLs) is also included in this chapter.
Chapter 2: Health Effects: Specific health effects identified in both human and animal studies are
reported by type of health effect (e.g., death, hepatic, renal, immune, reproductive), route of
exposure (e.g., inhalation, oral, dermal), and length of exposure (e.g., acute, intermediate, and
chronic).
NOTE: Not all health effects reported in this section are necessarily observed in the clinical
setting.
Pediatrics:
Section 3.2 Children and Other Populations that are Unusually Susceptible
Section 3.3 Biomarkers of Exposure and Effect
Case Studies in Environmental Medicine are self-instructional publications designed to increase primary
health care providers’ knowledge of a hazardous substance in the environment and to aid in the
evaluation of potentially exposed patients (see https://www.atsdr.cdc.gov/csem/csem.html).
Fact Sheets (ToxFAQs™) provide answers to frequently asked questions about toxic substances (see
https://www.atsdr.cdc.gov/toxfaqs/Index.asp).
GLYPHOSATE D-2
APPENDIX D
The National Center for Environmental Health (NCEH) focuses on preventing or controlling disease,
injury, and disability related to the interactions between people and their environment outside the
workplace. Contact: NCEH, Mailstop F-29, 4770 Buford Highway, NE, Atlanta, GA
30341-3724 • Phone: 770-488-7000 • FAX: 770-488-7015 • Web Page:
https://www.cdc.gov/nceh/.
The National Institute for Occupational Safety and Health (NIOSH) conducts research on occupational
diseases and injuries, responds to requests for assistance by investigating problems of health and
safety in the workplace, recommends standards to the Occupational Safety and Health
Administration (OSHA) and the Mine Safety and Health Administration (MSHA), and trains
professionals in occupational safety and health. Contact: NIOSH, 395 E Street, S.W., Suite 9200,
Patriots Plaza Building, Washington, DC 20201 • Phone: 202-245-0625 or 1-800-CDC-INFO
(800-232-4636) • Web Page: https://www.cdc.gov/niosh/.
The National Institute of Environmental Health Sciences (NIEHS) is the principal federal agency for
biomedical research on the effects of chemical, physical, and biologic environmental agents on
human health and well-being. Contact: NIEHS, PO Box 12233, 104 T.W. Alexander Drive,
Research Triangle Park, NC 27709 • Phone: 919-541-3212 • Web Page:
https://www.niehs.nih.gov/.
The Association of Occupational and Environmental Clinics (AOEC) has developed a network of clinics
in the United States to provide expertise in occupational and environmental issues. Contact:
AOEC, 1010 Vermont Avenue, NW, #513, Washington, DC 20005 • Phone: 202-347-4976
• FAX: 202-347-4950 • e-mail: AOEC@AOEC.ORG • Web Page: http://www.aoec.org/.
The American College of Medical Toxicology (ACMT) is a nonprofit association of physicians with
recognized expertise in medical toxicology. Contact: ACMT, 10645 North Tatum Boulevard,
Suite 200-111, Phoenix AZ 85028 • Phone: 844-226-8333 • FAX: 844-226-8333 • Web Page:
http://www.acmt.net.
The Pediatric Environmental Health Specialty Units (PEHSUs) is an interconnected system of specialists
who respond to questions from public health professionals, clinicians, policy makers, and the
public about the impact of environmental factors on the health of children and reproductive-aged
adults. Contact information for regional centers can be found at http://pehsu.net/findhelp.html.
The American Association of Poison Control Centers (AAPCC) provide support on the prevention and
treatment of poison exposures. Contact: AAPCC, 515 King Street, Suite 510, Alexandria VA
22314 • Phone: 701-894-1858 • Poison Help Line: 1-800-222-1222 • Web Page:
http://www.aapcc.org/.
GLYPHOSATE E-1
APPENDIX E. GLOSSARY
Absorption—The process by which a substance crosses biological membranes and enters systemic
circulation. Absorption can also refer to the taking up of liquids by solids, or of gases by solids or liquids.
Acute Exposure—Exposure to a chemical for a duration of ≤14 days, as specified in the Toxicological
Profiles.
Adsorption—The adhesion in an extremely thin layer of molecules (as of gases, solutes, or liquids) to the
surfaces of solid bodies or liquids with which they are in contact.
Adsorption Coefficient (Koc)—The ratio of the amount of a chemical adsorbed per unit weight of
organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium.
Adsorption Ratio (Kd)—The amount of a chemical adsorbed by sediment or soil (i.e., the solid phase)
divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a
fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or
sediment.
Cancer Effect Level (CEL)—The lowest dose of a chemical in a study, or group of studies, that
produces significant increases in the incidence of cancer (or tumors) between the exposed population and
its appropriate control.
Case-Control Study—A type of epidemiological study that examines the relationship between a
particular outcome (disease or condition) and a variety of potential causative agents (such as toxic
chemicals). In a case-control study, a group of people with a specified and well-defined outcome is
identified and compared to a similar group of people without the outcome.
Case Report—A report that describes a single individual with a particular disease or exposure. These
reports may suggest some potential topics for scientific research, but are not actual research studies.
GLYPHOSATE E-2
APPENDIX E
Case Series—Reports that describe the experience of a small number of individuals with the same
disease or exposure. These reports may suggest potential topics for scientific research, but are not actual
research studies.
Chronic Exposure—Exposure to a chemical for ≥365 days, as specified in the Toxicological Profiles.
Cohort Study—A type of epidemiological study of a specific group or groups of people who have had a
common insult (e.g., exposure to an agent suspected of causing disease or a common disease) and are
followed forward from exposure to outcome, and who are disease-free at start of follow-up. Often, at
least one exposed group is compared to one unexposed group, while in other cohorts, exposure is a
continuous variable and analyses are directed towards analyzing an exposure-response coefficient.
Cross-sectional Study—A type of epidemiological study of a group or groups of people that examines
the relationship between exposure and outcome to a chemical or to chemicals at a specific point in time.
Data Needs—Substance-specific informational needs that, if met, would reduce the uncertainties of
human health risk assessment.
Developmental Toxicity—The occurrence of adverse effects on the developing organism that may result
from exposure to a chemical prior to conception (either parent), during prenatal development, or
postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point
in the life span of the organism.
Embryotoxicity and Fetotoxicity—Any toxic effect on the conceptus as a result of prenatal exposure to
a chemical; the distinguishing feature between the two terms is the stage of development during which the
effect occurs. Effects include malformations and variations, altered growth, and in utero death.
Epidemiology—The investigation of factors that determine the frequency and distribution of disease or
other health-related conditions within a defined human population during a specified period.
Excretion—The process by which metabolic waste products are removed from the body.
Genotoxicity—A specific adverse effect on the genome of living cells that, upon the duplication of
affected cells, can be expressed as a mutagenic, clastogenic, or carcinogenic event because of specific
alteration of the molecular structure of the genome.
Half-life—A measure of rate for the time required to eliminate one-half of a quantity of a chemical from
the body or environmental media.
Health Advisory—An estimate of acceptable drinking water levels for a chemical substance derived by
EPA and based on health effects information. A health advisory is not a legally enforceable federal
standard, but serves as technical guidance to assist federal, state, and local officials.
GLYPHOSATE E-3
APPENDIX E
Immediately Dangerous to Life or Health (IDLH)—A condition that poses a threat of life or health, or
conditions that pose an immediate threat of severe exposure to contaminants that are likely to have
adverse cumulative or delayed effects on health.
Immunotoxicity—Adverse effect on the functioning of the immune system that may result from
exposure to chemical substances.
Incidence—The ratio of new cases of individuals in a population who develop a specified condition to
the total number of individuals in that population who could have developed that condition in a specified
time period.
In Vitro—Isolated from the living organism and artificially maintained, as in a test tube.
Lethal Concentration(LO) (LCLO)—The lowest concentration of a chemical in air that has been reported
to have caused death in humans or animals.
Lethal Concentration(50) (LC50)—A calculated concentration of a chemical in air to which exposure for
a specific length of time is expected to cause death in 50% of a defined experimental animal population.
Lethal Dose(LO) (LDLo)—The lowest dose of a chemical introduced by a route other than inhalation that
has been reported to have caused death in humans or animals.
Lethal Dose(50) (LD50)—The dose of a chemical that has been calculated to cause death in 50% of a
defined experimental animal population.
Lethal Time(50) (LT50)—A calculated period of time within which a specific concentration of a chemical
is expected to cause death in 50% of a defined experimental animal population.
Metabolism—Process in which chemical substances are biotransformed in the body that could result in
less toxic and/or readily excreted compounds or produce a biologically active intermediate.
Minimal Risk Level (MRL)—An estimate of daily human exposure to a hazardous substance that is
likely to be without an appreciable risk of adverse noncancer health effects over a specified route and
duration of exposure.
GLYPHOSATE E-4
APPENDIX E
Modifying Factor (MF)—A value (greater than zero) that is applied to the derivation of a Minimal Risk
Level (MRL) to reflect additional concerns about the database that are not covered by the uncertainty
factors. The default value for a MF is 1.
Morbidity—The state of being diseased; the morbidity rate is the incidence or prevalence of a disease in
a specific population.
Mortality—Death; the mortality rate is a measure of the number of deaths in a population during a
specified interval of time.
Mutagen—A substance that causes mutations, which are changes in the DNA sequence of a cell’s DNA.
Mutations can lead to birth defects, miscarriages, or cancer.
Necropsy—The gross examination of the organs and tissues of a dead body to determine the cause of
death or pathological conditions.
Odds Ratio (OR)—A means of measuring the association between an exposure (such as toxic substances
and a disease or condition) that represents the best estimate of relative risk (risk as a ratio of the incidence
among subjects exposed to a particular risk factor divided by the incidence among subjects who were not
exposed to the risk factor). An odds ratio that is greater than 1 is considered to indicate greater risk of
disease in the exposed group compared to the unexposed group.
Permissible Exposure Limit (PEL)—An Occupational Safety and Health Administration (OSHA)
regulatory limit on the amount or concentration of a substance not to be exceeded in workplace air
averaged over any 8-hour work shift of a 40-hour workweek.
Pesticide—General classification of chemicals specifically developed and produced for use in the control
of agricultural and public health pests (insects or other organisms harmful to cultivated plants or animals).
Pharmacokinetics—The dynamic behavior of a material in the body, used to predict the fate
(disposition) of an exogenous substance in an organism. Utilizing computational techniques, it provides
the means of studying the absorption, distribution, metabolism, and excretion of chemicals by the body.
Pharmacokinetic Model—A set of equations that can be used to describe the time course of a parent
chemical or metabolite in an animal system. There are two types of pharmacokinetic models: data-based
and physiologically-based. A data-based model divides the animal system into a series of compartments,
which, in general, do not represent real, identifiable anatomic regions of the body, whereas the
physiologically-based model compartments represent real anatomic regions of the body.
GLYPHOSATE E-5
APPENDIX E
Prospective Study—A type of cohort study in which a group is followed over time and the pertinent
observations are made on events occurring after the start of the study.
Recommended Exposure Limit (REL)—A National Institute for Occupational Safety and Health
(NIOSH) time-weighted average (TWA) concentration for up to a 10-hour workday during a 40-hour
workweek.
Reference Dose (RfD)—An estimate (with uncertainty spanning perhaps an order of magnitude) of the
daily oral exposure of the human population to a potential hazard that is likely to be without risk of
deleterious noncancer health effects during a lifetime. The oral RfD is expressed in units of mg/kg/day.
Reportable Quantity (RQ)—The quantity of a hazardous substance that is considered reportable under
the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). RQs are
(1) ≥1 pound or (2) for selected substances, an amount established by regulation either under CERCLA or
under Section 311 of the Clean Water Act. Quantities are measured over a 24-hour period.
Reproductive Toxicity—The occurrence of adverse effects on the reproductive system that may result
from exposure to a hazardous substance. The toxicity may be directed to the reproductive organs and/or
the related endocrine system. The manifestation of such toxicity may be noted as alterations in sexual
behavior, fertility, pregnancy outcomes, or modifications in other functions that are dependent on the
integrity of this system.
Retrospective Study—A type of cohort study based on a group of persons known to have been exposed
at some time in the past. Data are collected from routinely recorded events, up to the time the study is
undertaken. Retrospective studies are limited to causal factors that can be ascertained from existing
records and/or examining survivors of the cohort.
Risk—The possibility or chance that some adverse effect will result from a given exposure to a hazardous
substance.
GLYPHOSATE E-6
APPENDIX E
Risk Factor—An aspect of personal behavior or lifestyle, an environmental exposure, existing health
condition, or an inborn or inherited characteristic that is associated with an increased occurrence of
disease or other health-related event or condition.
Risk Ratio/Relative Risk—The ratio of the risk among persons with specific risk factors compared to the
risk among persons without risk factors. A risk ratio that is greater than 1 indicates greater risk of disease
in the exposed group compared to the unexposed group.
Short-Term Exposure Limit (STEL)—A STEL is a 15-minute TWA exposure that should not be
exceeded at any time during a workday.
Standardized Mortality Ratio (SMR)—A ratio of the observed number of deaths and the expected
number of deaths in a specific standard population.
Target Organ Toxicity—This term covers a broad range of adverse effects on target organs or
physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited
exposure to those assumed over a lifetime of exposure to a chemical.
Teratogen—A chemical that causes structural defects that affect the development of an organism.
Toxics Release Inventory (TRI)—The TRI is an EPA program that tracks toxic chemical releases and
pollution prevention activities reported by industrial and federal facilities.
Uncertainty Factor (UF)—A factor used in operationally deriving the Minimal Risk Level (MRL),
Reference Dose (RfD), or Reference Concentration (RfC) from experimental data. UFs are intended to
account for (1) the variation in sensitivity among the members of the human population, (2) the
uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating from
data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using lowest-
observed-adverse-effect level (LOAEL) data rather than no-observed-adverse-effect level (NOAEL) data.
A default for each individual UF is 10; if complete certainty in data exists, a value of 1 can be used;
however, a reduced UF of 3 may be used on a case-by-case basis (3 being the approximate logarithmic
average of 10 and 1).
APPENDIX F
APPENDIX F
APPENDIX F
APPENDIX F